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Dairy foods and risk of stroke: A meta-analysis of prospective cohort studies

Published:January 27, 2014DOI:https://doi.org/10.1016/j.numecd.2013.12.006

      Abstract

      Background and aims

      Epidemiological studies evaluating the association of dairy foods with risk of stroke have produced inconsistent results. We conducted a meta-analysis to summarize the evidence from prospective cohort studies regarding the association between dairy foods and risk of stroke.

      Methods and results

      Pertinent studies were identified by searching Embase (1950–November, 2013), Web of Knowledge (1950–November, 2013) and Pubmed (1945–November, 2013). Random-effect model was used to combine the results. Dose–response relationship was assessed by restricted cubic spline. Eighteen separate results from fifteen prospective cohort studies, with 28 138 stroke events among 764 635 participants, were included. Total dairy [relative risk (95% CI): 0.88 (0.82–0.94)], low-fat dairy [0.91 (0.85–0.97)], fermented milk [0.80 (0.71–0.89)] and cheese [0.94 (0.89–0.995)] were significantly associated with reduced risk of stroke, but whole/high-fat dairy, nonfermented milk, butter and cream were not significantly associated with risk of stroke. Stronger association was found for stroke mortality than incidence, and for studies conducted in Asia than Europe, while the association did not differ significantly by sex. Limited data did not find any significant association with either ischemic or hemorrhagic stroke. A non-linear dose–response relationship (P = 2.80*10−13) between milk and risk of stroke was found, and the relative risk of stroke was 0.88 (0.86–0.91), 0.82 (0.79–0.86), 0.83 (0.79–0.86), 0.85 (0.81–0.89), 0.86 (0.82–0.91), 0.91 (0.84–0.98) and 0.94 (0.86–1.02) for 100, 200, 300, 400, 500, 600 and 700 ml/day of milk, respectively.

      Conclusions

      Dairy foods might be inversely associated with the risk of stroke.

      Keywords

      Introduction

      Stroke is the fourth leading cause of global disease burden [
      • Lopez A.D.
      • Mathers C.D.
      • Ezzati M.
      • Jamison D.T.
      • Murray C.J.
      Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data.
      ]. Over the past four decades, stroke incidence declined by 42% in high-income countries but increased by 100% in low to middle income countries [
      • Feigin V.L.
      • Lawes C.M.
      • Bennett D.A.
      • Barker-Collo S.L.
      • Parag V.
      Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review.
      ]. About 87% of stroke deaths occurred in low to middle income countries, and the number of stroke deaths is projected to rise to 6.5 million in 2015 and to 7.8 million in 2030 globally without intervention [
      • Strong K.
      • Mathers C.
      • Bonita R.
      Preventing stroke: saving lives around the world.
      ]. According to American Heart Association, health behaviors including smoking, physical inactivity, nutrition, and overweight and obesity should be taken into account to reduce the risk of stroke [
      • Go A.S.
      • Mozaffarian D.
      • Roger V.L.
      • Benjamin E.J.
      • Berry J.D.
      • Borden W.B.
      • et al.
      Heart disease and stroke statistics–2013 update: a report from the American Heart Association.
      ]. Dairy foods are rich in saturated fatty acids, which can enhance cardiovascular disease by increasing cholesterol levels; however, dairy foods contribute many more compounds of health importance [
      • Pfeuffer M.
      • Schrezenmeir J.
      Milk and the metabolic syndrome.
      ]. Dairy foods are shown to have a potential benefit on risk of developing metabolic syndrome [
      • Pfeuffer M.
      • Schrezenmeir J.
      Milk and the metabolic syndrome.
      ,
      • Crichton G.E.
      • Bryan J.
      • Buckley J.
      • Murphy K.J.
      Dairy consumption and metabolic syndrome: a systematic review of findings and methodological issues.
      ], and a recent meta-analysis of prospective cohort studies suggested that total dairy, low-fat dairy and milk are significantly inversely associated with hypertension incidence [
      • Soedamah-Muthu S.S.
      • Verberne L.D.
      • Ding E.L.
      • Engberink M.F.
      • Geleijnse J.M.
      Dairy consumption and incidence of hypertension: a dose-response meta-analysis of prospective cohort studies.
      ]. In recent years, prospective cohort studies focusing on the relationship between dairy foods and risk of stroke have reported both positive [
      • Maruyama K.
      • Iso H.
      • Date C.
      • Kikuchi S.
      • Watanabe Y.
      • Wada Y.
      • et al.
      Dietary patterns and risk of cardiovascular deaths among middle-aged Japanese: JACC Study.
      ,
      • Sonestedt E.
      • Wirfalt E.
      • Wallstrom P.
      • Gullberg B.
      • Orho-Melander M.
      • Hedblad B.
      Dairy products and its association with incidence of cardiovascular disease: the Malmo diet and cancer cohort.
      ] and negative [
      • Dalmeijer G.W.
      • Struijk E.A.
      • van der Schouw Y.T.
      • Soedamah-Muthu S.S.
      • Verschuren W.M.
      • Boer J.M.
      • et al.
      Dairy intake and coronary heart disease or stroke – a population-based cohort study.
      ,
      • Kondo I.
      • Ojima T.
      • Nakamura M.
      • Hayasaka S.
      • Hozawa A.
      • Saitoh S.
      • et al.
      Consumption of dairy products and death from cardiovascular disease in the Japanese general population: the NIPPON DATA80.
      ,
      • Louie J.C.
      • Flood V.M.
      • Burlutsky G.
      • Rangan A.M.
      • Gill T.P.
      • Mitchell P.
      Dairy consumption and the risk of 15-year cardiovascular disease mortality in a cohort of older Australians.
      ] associations. However, findings from recent prospective cohort studies on dairy foods and risk of stroke have not been summarized systematically with a meta-analysis. Given studies with relatively small number of participants might be underpowered to detect the effect, and even small health effects of dairy foods on risk of stroke could have considerable public health consequences considering the popularity of dairy foods, thus we conducted a meta-analysis to (1) first assess the risk of stroke for the highest vs. lowest categories of dairy foods consumption; (2) then evaluate the possible dose–response relationship of dairy foods with risk of stroke when possible; (3) and assess the heterogeneity among studies and publication bias.

      Methods

      Literature search and selection

      We performed a literature search using the databases of Embase (1950–November, 2013), Web of Knowledge (1950–November, 2013) and Pubmed (1945–November, 2013), using the search term ((((((((dairy) OR milk) OR cheese) OR butter) OR cream) OR yogurt) OR yoghurt)) AND ((((cerebrovascular disease) OR cardiovascular disease) OR stroke) OR cerebral infarction) without restrictions. Moreover, we reviewed reference lists from retrieved articles to search for further relevant studies. Two investigators (DH and JQH) independently reviewed all identified studies, and studies were included if they met the following criteria: (1) a prospective cohort design; (2) the exposure of interest was dairy foods; (3) the outcome of interest was stroke; (4) relative risk (RR) with 95% confidence interval (CI) was provided. If data were duplicated in more than one study, we included the study with the largest number of cases.

      Data extraction

      The following data were extracted from each study by two investigators (DH and JQH): the first author's last name, publication year, follow-up duration, location where the study was performed, sample size and number of cases, type of dairy foods, RR (95% CI) for the highest vs. lowest categories of dairy foods, variables adjusted for in the analysis. For dose–response analysis, the number of cases and participants (person-years), and RR (95% CI) for each category of dairy foods were also extracted. The median or mean level of dairy foods for each category was assigned to the corresponding RR for every study. If upper boundary of the highest category was not provided, we assumed that the boundary had the same amplitude as the adjacent category. We extracted RRs that reflected the greatest degree of control for potential confounders.

      Statistical analysis

      Pooled measure was calculated as the inverse variance-weighted mean of the logarithm of RR with 95% CI to assess the strength of association. Random-effects model was used to combine study-specific RR (95%CI), which considers both within-study and between-study variation. Heterogeneity was assessed quantitatively with I2, and I2 values of 25, 50 and 75% represent low, moderate and high heterogeneity [
      • Higgins J.P.
      • Thompson S.G.
      • Deeks J.J.
      • Altman D.G.
      Measuring inconsistency in meta-analyses.
      ], respectively. Sensitivity analysis was performed with one study removed at a time, [
      • Tobias A.
      Assessing the influence of a single study in the meta-analysis estimate.
      ] and a study is excessively influential if the significance of its “omitted” meta-analytic estimate differed relative to the overall estimate. Publication bias was evaluated using Egger regression asymmetry test [
      • Egger M.
      • Davey Smith G.
      • Schneider M.
      • Minder C.
      Bias in meta-analysis detected by a simple, graphical test.
      ]. Meta-regression was performed to assess the potential sources of between-study heterogeneity [
      • Higgins J.P.
      • Thompson S.G.
      Controlling the risk of spurious findings from meta-regression.
      ]. Study quality was assessed using the 9-star Newcastle–Ottawa Scale (http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp, accessed 10/14/2013).
      For the association of total dairy foods with risk of stroke, we first combined the results within each study if two or more types of dairy foods were reported. The result for male and female was included as two separate results. Butter, cream, ice cream and whole/high-fat milk were included in the whole/high-fat dairy foods group.
      A two-stage random-effects dose–response meta-analysis [
      • Orsini N.
      • Li R.
      • Wolk A.
      • Khudyakov P.
      • Spiegelman D.
      Meta-analysis for linear and nonlinear dose-response relations: examples, an evaluation of approximations, and software.
      ] was performed to compute the trend from the correlated log RR estimates across levels of dairy foods, taking into account the between-study heterogeneity. In the first stage, a restricted cubic spline model with three knots at 25th, 50th and 75th percentiles of the levels of dairy foods was estimated using generalized least-square regression. Then the study-specific estimates were combined using the restricted maximum likelihood method in a multivariate random-effects meta-analysis. A P-value for non-linearity was calculated by testing the null hypothesis that the coefficient of the second spline is equal to 0. Dose–response analysis was conducted when more than 3 separate results were available. All statistical analyses were performed with STATA version 12.0, with P < 0.05 considered statistically significant.

      Results

      Literature search and study characteristics

      Procedure of literature search was shown in Supplementary Fig. 1. Two case–control studies and one study did not provide the RR (95%CI) were also excluded. Three studies [
      • Iso H.
      • Stampfer M.J.
      • Manson J.E.
      • Rexrode K.
      • Hennekens C.H.
      • Colditz G.A.
      • et al.
      Prospective study of calcium, potassium, and magnesium intake and risk of stroke in women.
      ,
      • He K.
      • Merchant A.
      • Rimm E.B.
      • Rosner B.A.
      • Stampfer M.J.
      • Willett W.C.
      • et al.
      Dietary fat intake and risk of stroke in male US healthcare professionals: 14 year prospective cohort study.
      ,
      • Elwood P.C.
      • Strain J.J.
      • Robson P.J.
      • Fehily A.M.
      • Hughes J.
      • Pickering J.
      • et al.
      Milk consumption, stroke, and heart attack risk: evidence from the Caerphilly cohort of older men.
      ] were further excluded because of duplicate reports from the same study population [
      • Bernstein A.M.
      • Pan A.
      • Rexrode K.M.
      • Stampfer M.
      • Hu F.B.
      • Mozaffarian D.
      • et al.
      Dietary protein sources and the risk of stroke in men and women.
      ,
      • Elwood P.C.
      • Pickering J.E.
      • Fehily A.M.
      • Hughes J.
      • Ness A.R.
      Milk drinking, ischaemic heart disease and ischaemic stroke I. Evidence from the Caerphilly cohort.
      ]. Finally, eighteen separate results from fifteen prospective cohort studies were included [2 separate results (male and female) were available in 3 studies [
      • Maruyama K.
      • Iso H.
      • Date C.
      • Kikuchi S.
      • Watanabe Y.
      • Wada Y.
      • et al.
      Dietary patterns and risk of cardiovascular deaths among middle-aged Japanese: JACC Study.
      ,
      • Kondo I.
      • Ojima T.
      • Nakamura M.
      • Hayasaka S.
      • Hozawa A.
      • Saitoh S.
      • et al.
      Consumption of dairy products and death from cardiovascular disease in the Japanese general population: the NIPPON DATA80.
      ,
      • Goldbohm R.A.
      • Chorus A.M.
      • Galindo Garre F.
      • Schouten L.J.
      • van den Brandt P.A.
      Dairy consumption and 10-y total and cardiovascular mortality: a prospective cohort study in the Netherlands.
      ]] (Table 1).
      Table 1Characteristics of studies included on dairy foods and stroke.
      AuthorStudy, countryAge at baseline (years)Subjects (cases)SexQuality scoreFollow-up yearsOutcomeExposureRR (95% CI) for the highest vs. lowest categoriesCovariates adjusted
      Dalmeijer et al., 2013
      • Dalmeijer G.W.
      • Struijk E.A.
      • van der Schouw Y.T.
      • Soedamah-Muthu S.S.
      • Verschuren W.M.
      • Boer J.M.
      • et al.
      Dairy intake and coronary heart disease or stroke – a population-based cohort study.
      EPIC-NL Study, Netherlands49–7033 625 (531)Both713IncidenceTotal dairy0.95 (0.85–1.05)Gender, age, total energy intake, physical activity, smoking, education, BMI, intake of ethanol, coffee, fruit, vegetables, fish, meat and bread
      Milk and milk products0.95 (0.86–1.05)
      Cheese0.96 (0.88–1.06)
      High-fat dairy0.99 (0.91–1.09)
      Low-fat dairy0.94 (0.85–1.03)
      Lin et al., 2013
      • Lin P.H.
      • Yeh W.T.
      • Svetkey L.P.
      • Chuang S.Y.
      • Chang Y.C.
      • Wang C.
      • et al.
      Dietary intakes consistent with the DASH dietary pattern reduce blood pressure increase with age and risk for stroke in a Chinese population.
      CVDFACTS, China32–602061 (123)Both713IncidenceTotal dairy0.74 (0.48–1.14)Sex, age, urinary sodium/creatinine, smoking status, drinking status, physical activity, BMI, SBP change, DBP change, and hypertension medication
      Kondo et al., 2013
      • Kondo I.
      • Ojima T.
      • Nakamura M.
      • Hayasaka S.
      • Hozawa A.
      • Saitoh S.
      • et al.
      Consumption of dairy products and death from cardiovascular disease in the Japanese general population: the NIPPON DATA80.
      NIPPON DATA80, Japan≥304045 (217)M824MortalityTotal dairy0.91 (0.67–1.25)Age, BMI, smoking status, alcohol, history of diabetes, use of antihypertensives, work category and total energy intake
      5198 (200)F0.75 (0.53–1.06)
      Louie et al., 2013
      • Louie J.C.
      • Flood V.M.
      • Burlutsky G.
      • Rangan A.M.
      • Gill T.P.
      • Mitchell P.
      Dairy consumption and the risk of 15-year cardiovascular disease mortality in a cohort of older Australians.
      BMES, Australia49–972900 (176)Both715MortalityTotal dairy0.98 (0.58–1.16)Age, sex, total energy, baseline BMI, change in weight during follow up, physical activity level, previous acute myocardial infarction, previous stroke, smoking, stage II hypertension, T2DM status, use of antihypertensive medication, use of statins and change in dairy intake
      Low/reduced fat dairy0.84 (0.52–1.37)
      Whole fat dairy1.01 (0.64–1.64)
      Maruyama et al., 2013
      • Maruyama K.
      • Iso H.
      • Date C.
      • Kikuchi S.
      • Watanabe Y.
      • Wada Y.
      • et al.
      Dietary patterns and risk of cardiovascular deaths among middle-aged Japanese: JACC Study.
      JACC Study, Japan40–7926 598 (272)M713MortalityTotal dairy0.65 (0.49–0.86)Age, BMI, smoking, walking time, hours of sports, education, perceived mental stress, sleep duration, total energy intake, history of hypertension and diabetes
      37 439 (207)F0.70 (0.51–0.97)
      Bernstein et al., 2012
      • Bernstein A.M.
      • Pan A.
      • Rexrode K.M.
      • Stampfer M.
      • Hu F.B.
      • Mozaffarian D.
      • et al.
      Dietary protein sources and the risk of stroke in men and women.
      HFPS, USA40–7543 150 (1397)M822IncidenceWhole-fat dairy0.87 (0.72–1.06)Age, time period, BMI, smoking, physical exercise, parental history of early myocardial infarction, menopausal status in women, multivitamin use, vitamin E supplement use, aspirin use, total energy, cereal fiber, alcohol, transfat, fruit and vegetables, and other protein sources
      Low-fat dairy0.94 (0.78–1.12)
      NHS, USA30–5584 010 (2633)F26Whole-fat dairy0.90 (0.79–1.03)
      Low-fat dairy0.91 (0.79–1.04)
      Larsson et al., 2012
      • Larsson S.C.
      • Virtamo J.
      • Wolk A.
      Dairy consumption and risk of stroke in Swedish women and men.
      The Swedish Mammography Cohort and the Cohort of Swedish Men, Sweden45–8374 961 (4089)Both810.2IncidenceTotal dairy0.91 (0.80–1.03)Age, sex, smoking status, and pack-y of smoking, education, BMI, total physical activity, aspirin use, history of hypertension, diabetes, family history of myocardial infarction, intakes of total energy, alcohol, coffee, fresh red meat, processed meat, fish, fruits, and vegetables. Individual dairy foods were mutually adjusted
      Low-fat dairy0.88 (0.80–0.97)
      Full-fat dairy0.94 (0.83–1.07)
      Milk0.90 (0.82–1.00)
      Sour milk and yogurt0.98 (0.90–1.08)
      Cheese0.91 (0.81–1.01)
      Cream and creme fraiche1.00 (0.89–1.12)
      Sonestedt et al., 2011
      • Sonestedt E.
      • Wirfalt E.
      • Wallstrom P.
      • Gullberg B.
      • Orho-Melander M.
      • Hedblad B.
      Dairy products and its association with incidence of cardiovascular disease: the Malmo diet and cancer cohort.
      Malmo Diet and Cancer Cohort, Sweden44–7426 445 (1176)Both812IncidenceTotal dairy0.91 (0.75–1.09)Age, sex, season, method, energy intake, BMI, smoking, alcohol consumption, leisure-time physical activity, education
      Milk0.91 (0.76–1.10)
      Non-fermented milk0.96 (0.80–1.15)
      Fermented milk0.80 (0.68–0.95)
      Low-fat milk0.76 (0.63–0.91)
      High-fat milk1.17 (0.97–1.40)
      Cheese0.96 (0.80–1.15)
      Butter0.92 (0.78–1.10)
      Cream0.97 (0.81–1.16)
      Goldbohm et al.,
      • Goldbohm R.A.
      • Chorus A.M.
      • Galindo Garre F.
      • Schouten L.J.
      • van den Brandt P.A.
      Dairy consumption and 10-y total and cardiovascular mortality: a prospective cohort study in the Netherlands.
      Netherlands Cohort Study, Netherlands55–6958 279 (520)M810MortalityMilk productsM: 0.80 (0.52–1.25)Age, education, cigarette, cigar and pipe (men only), smoking, nonoccupational physical activity, occupational physical activity, BMI, multivitamin use, alcohol, energy, energy-adjusted mono- and polyunsaturated fat intakes, and vegetable and fruit consumption
      62 573 (322)FF: 0.95 (0.60–1.49)
      Nonfermented full-fat milkM: 0.96 (0.60–1.54)
      F: 1.33 (0.87–2.01)
      Nonfermented low-fat milkM: 1.17 (0.87–1.57)
      F: 0.90 (0.65–1.24)
      Fermented full-fat milkM: 0.82 (0.59–1.15)
      F: 0.85 (0.62–1.18)
      Fermented low-fat milkM: 0.79 (0.56–1.10)
      F: 0.68 (0.47–0.98)
      CheeseM: 1.12 (0.70–1.77)
      F: 0.65 (0.39–1.10)
      ButterM: 0.87 (0.64–1.18)
      F: 0.90 (0.64–1.27)
      Low-fat dairyM: 1.03 (0.68–1.55)
      F: 0.77 (0.48–1.22)
      van der Pols et al., 2009
      • van der Pols J.C.
      • Gunnell D.
      • Williams G.M.
      • Holly J.M.
      • Bain C.
      • Martin R.M.
      Childhood dairy and calcium intake and cardiovascular mortality in adulthood: 65-year follow-up of the Boyd Orr cohort.
      The Boyd Orr Cohort, England and Scotland84999 (121)Both865MortalityTotal dairy0.74 (0.24–2.22)Age, sex, survey district, intake of fruit, vegetable, egg and egg dishes, protein, fat and energy intake, household food expenditure in childhood, Townsend deprivation score in adulthood and calcium
      Milk0.76 (0.26–2.19)
      Larsson et al., 2009
      • Larsson S.C.
      • Mannisto S.
      • Virtanen M.J.
      • Kontto J.
      • Albanes D.
      • Virtamo J.
      Dairy foods and risk of stroke.
      The ATBC Study, Finland50–6926 556 (3281)M (smokers)713.6IncidenceTotal dairy1.17 (1.03–1.36)Age, supplementation group, education, cigarettes smoked daily, BMI, serum total cholesterol, serum HDL cholesterol, histories of diabetes and heart disease, leisure-time physical activity, intakes of total energy, alcohol, caffeine, sugar, red meat, poultry, fish, fruit, fruit juices, vegetables, potatoes, whole grains, and refined grains
      Low fat milk1.04 (0.93–1.17)
      Whole milk1.15 (0.99–1.34)
      Sour milk0.97 (0.82–1.16)
      Yogurt1.17 (0.83–1.64)
      Cheese0.94 (0.83–1.06)
      Cream0.84 (0.67–1.05)
      Ice cream0.99 (0.84–1.16)
      Butter1.10 (0.87–1.39)
      Elwood et al., 2004
      • Elwood P.C.
      • Pickering J.E.
      • Fehily A.M.
      • Hughes J.
      • Ness A.R.
      Milk drinking, ischaemic heart disease and ischaemic stroke I. Evidence from the Caerphilly cohort.
      The Caerphilly Cohort Study, UK45–592512 (185)M720–24IncidenceMilk0.66 (0.24–1.81)Age, energy, smoking, social class, BMI, systolic blood pressure, consumption of alcohol and fat and prior vascular disease
      Sauvaget et al., 2003
      • Sauvaget C.
      • Nagano J.
      • Allen N.
      • Grant E.J.
      • Beral V.
      Intake of animal products and stroke mortality in the Hiroshima/Nagasaki Life Span Study.
      The Life Span Study, Japan34–10340 349 (1462)Both716MortalityMilk0.94 (0.79–1.12)Sex, birth cohort, city, radiation dose, self-reported BMI, smoking status, alcohol habits, education level, history of diabetes, or hypertension
      Dairy products0.73 (0.57–0.94)
      Ness et al., 2001
      • Ness A.R.
      • Smith G.D.
      • Hart C.
      Milk, coronary heart disease and mortality.
      The Collaborative Study, Scotland35–645765 (196)M725MortalityMilk0.84 (0.31–2.30)Age, smoking, DBP, cholesterol, BMI, adjusted FEV1, social class, father's social class, education, deprivation category, siblings, caruser, angina, ECG ischemia, bronchitis and alcohol
      Kinjo et al., 1999
      • Kinjo Y.
      • Beral V.
      • Akiba S.
      • Key T.
      • Mizuno S.
      • Appleby P.
      • et al.
      Possible protective effect of milk, meat and fish for cerebrovascular disease mortality in Japan.
      None, Japan40–69223 170 (11 030)Both616MortalityMilk0.79 (0.75–0.83)Sex, attained age, follow-up interval, prefecture, alcohol drinking, smoking and occupation
      BMI: body mass index, DBP: diastolic blood pressure, FEV1: forced expiratory volume in 1 s, ECG: electrocardiograph, HDL: high-density lipoprotein, T2DM: type 2 diabetes mellitus, M: male, F, female.
      Eight [
      • Maruyama K.
      • Iso H.
      • Date C.
      • Kikuchi S.
      • Watanabe Y.
      • Wada Y.
      • et al.
      Dietary patterns and risk of cardiovascular deaths among middle-aged Japanese: JACC Study.
      ,
      • Kondo I.
      • Ojima T.
      • Nakamura M.
      • Hayasaka S.
      • Hozawa A.
      • Saitoh S.
      • et al.
      Consumption of dairy products and death from cardiovascular disease in the Japanese general population: the NIPPON DATA80.
      ,
      • Louie J.C.
      • Flood V.M.
      • Burlutsky G.
      • Rangan A.M.
      • Gill T.P.
      • Mitchell P.
      Dairy consumption and the risk of 15-year cardiovascular disease mortality in a cohort of older Australians.
      ,
      • Goldbohm R.A.
      • Chorus A.M.
      • Galindo Garre F.
      • Schouten L.J.
      • van den Brandt P.A.
      Dairy consumption and 10-y total and cardiovascular mortality: a prospective cohort study in the Netherlands.
      ,
      • van der Pols J.C.
      • Gunnell D.
      • Williams G.M.
      • Holly J.M.
      • Bain C.
      • Martin R.M.
      Childhood dairy and calcium intake and cardiovascular mortality in adulthood: 65-year follow-up of the Boyd Orr cohort.
      ,
      • Sauvaget C.
      • Nagano J.
      • Allen N.
      • Grant E.J.
      • Beral V.
      Intake of animal products and stroke mortality in the Hiroshima/Nagasaki Life Span Study.
      ,
      • Ness A.R.
      • Smith G.D.
      • Hart C.
      Milk, coronary heart disease and mortality.
      ,
      • Kinjo Y.
      • Beral V.
      • Akiba S.
      • Key T.
      • Mizuno S.
      • Appleby P.
      • et al.
      Possible protective effect of milk, meat and fish for cerebrovascular disease mortality in Japan.
      ] of the fifteen prospective cohort studies focused on dairy foods and stroke mortality, and the other seven [
      • Sonestedt E.
      • Wirfalt E.
      • Wallstrom P.
      • Gullberg B.
      • Orho-Melander M.
      • Hedblad B.
      Dairy products and its association with incidence of cardiovascular disease: the Malmo diet and cancer cohort.
      ,
      • Dalmeijer G.W.
      • Struijk E.A.
      • van der Schouw Y.T.
      • Soedamah-Muthu S.S.
      • Verschuren W.M.
      • Boer J.M.
      • et al.
      Dairy intake and coronary heart disease or stroke – a population-based cohort study.
      ,
      • Bernstein A.M.
      • Pan A.
      • Rexrode K.M.
      • Stampfer M.
      • Hu F.B.
      • Mozaffarian D.
      • et al.
      Dietary protein sources and the risk of stroke in men and women.
      ,
      • Elwood P.C.
      • Pickering J.E.
      • Fehily A.M.
      • Hughes J.
      • Ness A.R.
      Milk drinking, ischaemic heart disease and ischaemic stroke I. Evidence from the Caerphilly cohort.
      ,
      • Larsson S.C.
      • Virtamo J.
      • Wolk A.
      Dairy consumption and risk of stroke in Swedish women and men.
      ,
      • Larsson S.C.
      • Mannisto S.
      • Virtanen M.J.
      • Kontto J.
      • Albanes D.
      • Virtamo J.
      Dairy foods and risk of stroke.
      ,
      • Lin P.H.
      • Yeh W.T.
      • Svetkey L.P.
      • Chuang S.Y.
      • Chang Y.C.
      • Wang C.
      • et al.
      Dietary intakes consistent with the DASH dietary pattern reduce blood pressure increase with age and risk for stroke in a Chinese population.
      ] focused on dairy foods and stroke incidence. Most of the studies adjusted results for the known risk factors of stroke like smoking (but 1 study [
      • van der Pols J.C.
      • Gunnell D.
      • Williams G.M.
      • Holly J.M.
      • Bain C.
      • Martin R.M.
      Childhood dairy and calcium intake and cardiovascular mortality in adulthood: 65-year follow-up of the Boyd Orr cohort.
      ]), body mass index (BMI, but 2 studies [
      • van der Pols J.C.
      • Gunnell D.
      • Williams G.M.
      • Holly J.M.
      • Bain C.
      • Martin R.M.
      Childhood dairy and calcium intake and cardiovascular mortality in adulthood: 65-year follow-up of the Boyd Orr cohort.
      ,
      • Kinjo Y.
      • Beral V.
      • Akiba S.
      • Key T.
      • Mizuno S.
      • Appleby P.
      • et al.
      Possible protective effect of milk, meat and fish for cerebrovascular disease mortality in Japan.
      ]), total energy intake (but 3 studies [
      • Sauvaget C.
      • Nagano J.
      • Allen N.
      • Grant E.J.
      • Beral V.
      Intake of animal products and stroke mortality in the Hiroshima/Nagasaki Life Span Study.
      ,
      • Ness A.R.
      • Smith G.D.
      • Hart C.
      Milk, coronary heart disease and mortality.
      ,
      • Kinjo Y.
      • Beral V.
      • Akiba S.
      • Key T.
      • Mizuno S.
      • Appleby P.
      • et al.
      Possible protective effect of milk, meat and fish for cerebrovascular disease mortality in Japan.
      ]) and alcohol (but 3 studies [
      • Maruyama K.
      • Iso H.
      • Date C.
      • Kikuchi S.
      • Watanabe Y.
      • Wada Y.
      • et al.
      Dietary patterns and risk of cardiovascular deaths among middle-aged Japanese: JACC Study.
      ,
      • Louie J.C.
      • Flood V.M.
      • Burlutsky G.
      • Rangan A.M.
      • Gill T.P.
      • Mitchell P.
      Dairy consumption and the risk of 15-year cardiovascular disease mortality in a cohort of older Australians.
      ,
      • Elwood P.C.
      • Pickering J.E.
      • Fehily A.M.
      • Hughes J.
      • Ness A.R.
      Milk drinking, ischaemic heart disease and ischaemic stroke I. Evidence from the Caerphilly cohort.
      ]). Six studies adjusted for more than 3 other dietary factors [
      • Dalmeijer G.W.
      • Struijk E.A.
      • van der Schouw Y.T.
      • Soedamah-Muthu S.S.
      • Verschuren W.M.
      • Boer J.M.
      • et al.
      Dairy intake and coronary heart disease or stroke – a population-based cohort study.
      ,
      • Bernstein A.M.
      • Pan A.
      • Rexrode K.M.
      • Stampfer M.
      • Hu F.B.
      • Mozaffarian D.
      • et al.
      Dietary protein sources and the risk of stroke in men and women.
      ,
      • Goldbohm R.A.
      • Chorus A.M.
      • Galindo Garre F.
      • Schouten L.J.
      • van den Brandt P.A.
      Dairy consumption and 10-y total and cardiovascular mortality: a prospective cohort study in the Netherlands.
      ,
      • van der Pols J.C.
      • Gunnell D.
      • Williams G.M.
      • Holly J.M.
      • Bain C.
      • Martin R.M.
      Childhood dairy and calcium intake and cardiovascular mortality in adulthood: 65-year follow-up of the Boyd Orr cohort.
      ,
      • Larsson S.C.
      • Virtamo J.
      • Wolk A.
      Dairy consumption and risk of stroke in Swedish women and men.
      ,
      • Larsson S.C.
      • Mannisto S.
      • Virtanen M.J.
      • Kontto J.
      • Albanes D.
      • Virtamo J.
      Dairy foods and risk of stroke.
      ], and nine studies adjusted for physical activity [
      • Maruyama K.
      • Iso H.
      • Date C.
      • Kikuchi S.
      • Watanabe Y.
      • Wada Y.
      • et al.
      Dietary patterns and risk of cardiovascular deaths among middle-aged Japanese: JACC Study.
      ,
      • Sonestedt E.
      • Wirfalt E.
      • Wallstrom P.
      • Gullberg B.
      • Orho-Melander M.
      • Hedblad B.
      Dairy products and its association with incidence of cardiovascular disease: the Malmo diet and cancer cohort.
      ,
      • Dalmeijer G.W.
      • Struijk E.A.
      • van der Schouw Y.T.
      • Soedamah-Muthu S.S.
      • Verschuren W.M.
      • Boer J.M.
      • et al.
      Dairy intake and coronary heart disease or stroke – a population-based cohort study.
      ,
      • Louie J.C.
      • Flood V.M.
      • Burlutsky G.
      • Rangan A.M.
      • Gill T.P.
      • Mitchell P.
      Dairy consumption and the risk of 15-year cardiovascular disease mortality in a cohort of older Australians.
      ,
      • Bernstein A.M.
      • Pan A.
      • Rexrode K.M.
      • Stampfer M.
      • Hu F.B.
      • Mozaffarian D.
      • et al.
      Dietary protein sources and the risk of stroke in men and women.
      ,
      • Goldbohm R.A.
      • Chorus A.M.
      • Galindo Garre F.
      • Schouten L.J.
      • van den Brandt P.A.
      Dairy consumption and 10-y total and cardiovascular mortality: a prospective cohort study in the Netherlands.
      ,
      • Larsson S.C.
      • Virtamo J.
      • Wolk A.
      Dairy consumption and risk of stroke in Swedish women and men.
      ,
      • Larsson S.C.
      • Mannisto S.
      • Virtanen M.J.
      • Kontto J.
      • Albanes D.
      • Virtamo J.
      Dairy foods and risk of stroke.
      ,
      • Lin P.H.
      • Yeh W.T.
      • Svetkey L.P.
      • Chuang S.Y.
      • Chang Y.C.
      • Wang C.
      • et al.
      Dietary intakes consistent with the DASH dietary pattern reduce blood pressure increase with age and risk for stroke in a Chinese population.
      ]. Dairy foods were estimated using weighed diet records for 3 consecutive days [
      • Kondo I.
      • Ojima T.
      • Nakamura M.
      • Hayasaka S.
      • Hozawa A.
      • Saitoh S.
      • et al.
      Consumption of dairy products and death from cardiovascular disease in the Japanese general population: the NIPPON DATA80.
      ], 7-day household inventory method [
      • van der Pols J.C.
      • Gunnell D.
      • Williams G.M.
      • Holly J.M.
      • Bain C.
      • Martin R.M.
      Childhood dairy and calcium intake and cardiovascular mortality in adulthood: 65-year follow-up of the Boyd Orr cohort.
      ], and self-administered food frequency questionnaire in the other thirteen studies. All studies had a mean follow-up duration of 10 years or more. Only the association of milk consumption with risk of stroke could be assessed in dose–response analysis, because of limited results available for the other analysis.

      Quantitative synthesis

      (The main results are summarized in Table 2).
      Table 2Summary risk estimates of the association between dairy foods and risk of stroke.
      N
      N: number of results; 2 separate results (male and female) were available in 3 studies [8,11,23].
      Number of casesRisk estimate (95% CI)Heterogeneity testReferences
      REMPI2 (%)PP
      P value for meta-regression, and location where the study was conducted (Europe as the reference) and specific types (milk as the reference) were included as dummy variables in meta-regression.
      Total dairy1828 1380.88 (0.82–0.94)0.0061.80.00
      Outcome0.01
       Incidence713 4150.95 (0.87–1.03)0.2350.90.06
      • Sonestedt E.
      • Wirfalt E.
      • Wallstrom P.
      • Gullberg B.
      • Orho-Melander M.
      • Hedblad B.
      Dairy products and its association with incidence of cardiovascular disease: the Malmo diet and cancer cohort.
      ,
      • Dalmeijer G.W.
      • Struijk E.A.
      • van der Schouw Y.T.
      • Soedamah-Muthu S.S.
      • Verschuren W.M.
      • Boer J.M.
      • et al.
      Dairy intake and coronary heart disease or stroke – a population-based cohort study.
      ,
      • Bernstein A.M.
      • Pan A.
      • Rexrode K.M.
      • Stampfer M.
      • Hu F.B.
      • Mozaffarian D.
      • et al.
      Dietary protein sources and the risk of stroke in men and women.
      ,
      • Elwood P.C.
      • Pickering J.E.
      • Fehily A.M.
      • Hughes J.
      • Ness A.R.
      Milk drinking, ischaemic heart disease and ischaemic stroke I. Evidence from the Caerphilly cohort.
      ,
      • Larsson S.C.
      • Virtamo J.
      • Wolk A.
      Dairy consumption and risk of stroke in Swedish women and men.
      ,
      • Larsson S.C.
      • Mannisto S.
      • Virtanen M.J.
      • Kontto J.
      • Albanes D.
      • Virtamo J.
      Dairy foods and risk of stroke.
      ,
      • Lin P.H.
      • Yeh W.T.
      • Svetkey L.P.
      • Chuang S.Y.
      • Chang Y.C.
      • Wang C.
      • et al.
      Dietary intakes consistent with the DASH dietary pattern reduce blood pressure increase with age and risk for stroke in a Chinese population.
       Mortality1114 7230.80 (0.76–0.84)0.000.000.65
      • Maruyama K.
      • Iso H.
      • Date C.
      • Kikuchi S.
      • Watanabe Y.
      • Wada Y.
      • et al.
      Dietary patterns and risk of cardiovascular deaths among middle-aged Japanese: JACC Study.
      ,
      • Kondo I.
      • Ojima T.
      • Nakamura M.
      • Hayasaka S.
      • Hozawa A.
      • Saitoh S.
      • et al.
      Consumption of dairy products and death from cardiovascular disease in the Japanese general population: the NIPPON DATA80.
      ,
      • Louie J.C.
      • Flood V.M.
      • Burlutsky G.
      • Rangan A.M.
      • Gill T.P.
      • Mitchell P.
      Dairy consumption and the risk of 15-year cardiovascular disease mortality in a cohort of older Australians.
      ,
      • Goldbohm R.A.
      • Chorus A.M.
      • Galindo Garre F.
      • Schouten L.J.
      • van den Brandt P.A.
      Dairy consumption and 10-y total and cardiovascular mortality: a prospective cohort study in the Netherlands.
      ,
      • van der Pols J.C.
      • Gunnell D.
      • Williams G.M.
      • Holly J.M.
      • Bain C.
      • Martin R.M.
      Childhood dairy and calcium intake and cardiovascular mortality in adulthood: 65-year follow-up of the Boyd Orr cohort.
      ,
      • Sauvaget C.
      • Nagano J.
      • Allen N.
      • Grant E.J.
      • Beral V.
      Intake of animal products and stroke mortality in the Hiroshima/Nagasaki Life Span Study.
      ,
      • Ness A.R.
      • Smith G.D.
      • Hart C.
      Milk, coronary heart disease and mortality.
      ,
      • Kinjo Y.
      • Beral V.
      • Akiba S.
      • Key T.
      • Mizuno S.
      • Appleby P.
      • et al.
      Possible protective effect of milk, meat and fish for cerebrovascular disease mortality in Japan.
      Location where the study was conducted
       Europe910 4210.95 (0.88–1.03)0.2430.40.181.00
      • Sonestedt E.
      • Wirfalt E.
      • Wallstrom P.
      • Gullberg B.
      • Orho-Melander M.
      • Hedblad B.
      Dairy products and its association with incidence of cardiovascular disease: the Malmo diet and cancer cohort.
      ,
      • Dalmeijer G.W.
      • Struijk E.A.
      • van der Schouw Y.T.
      • Soedamah-Muthu S.S.
      • Verschuren W.M.
      • Boer J.M.
      • et al.
      Dairy intake and coronary heart disease or stroke – a population-based cohort study.
      ,
      • Elwood P.C.
      • Pickering J.E.
      • Fehily A.M.
      • Hughes J.
      • Ness A.R.
      Milk drinking, ischaemic heart disease and ischaemic stroke I. Evidence from the Caerphilly cohort.
      ,
      • Goldbohm R.A.
      • Chorus A.M.
      • Galindo Garre F.
      • Schouten L.J.
      • van den Brandt P.A.
      Dairy consumption and 10-y total and cardiovascular mortality: a prospective cohort study in the Netherlands.
      ,
      • van der Pols J.C.
      • Gunnell D.
      • Williams G.M.
      • Holly J.M.
      • Bain C.
      • Martin R.M.
      Childhood dairy and calcium intake and cardiovascular mortality in adulthood: 65-year follow-up of the Boyd Orr cohort.
      ,
      • Ness A.R.
      • Smith G.D.
      • Hart C.
      Milk, coronary heart disease and mortality.
      ,
      • Larsson S.C.
      • Virtamo J.
      • Wolk A.
      Dairy consumption and risk of stroke in Swedish women and men.
      ,
      • Larsson S.C.
      • Mannisto S.
      • Virtanen M.J.
      • Kontto J.
      • Albanes D.
      • Virtamo J.
      Dairy foods and risk of stroke.
       Asia713 5110.79 (0.75–0.82)0.000.000.740.00
      • Maruyama K.
      • Iso H.
      • Date C.
      • Kikuchi S.
      • Watanabe Y.
      • Wada Y.
      • et al.
      Dietary patterns and risk of cardiovascular deaths among middle-aged Japanese: JACC Study.
      ,
      • Kondo I.
      • Ojima T.
      • Nakamura M.
      • Hayasaka S.
      • Hozawa A.
      • Saitoh S.
      • et al.
      Consumption of dairy products and death from cardiovascular disease in the Japanese general population: the NIPPON DATA80.
      ,
      • Sauvaget C.
      • Nagano J.
      • Allen N.
      • Grant E.J.
      • Beral V.
      Intake of animal products and stroke mortality in the Hiroshima/Nagasaki Life Span Study.
      ,
      • Kinjo Y.
      • Beral V.
      • Akiba S.
      • Key T.
      • Mizuno S.
      • Appleby P.
      • et al.
      Possible protective effect of milk, meat and fish for cerebrovascular disease mortality in Japan.
      ,
      • Lin P.H.
      • Yeh W.T.
      • Svetkey L.P.
      • Chuang S.Y.
      • Chang Y.C.
      • Wang C.
      • et al.
      Dietary intakes consistent with the DASH dietary pattern reduce blood pressure increase with age and risk for stroke in a Chinese population.
       Others242060.91 (0.85–0.99)0.020.000.680.59
      • Louie J.C.
      • Flood V.M.
      • Burlutsky G.
      • Rangan A.M.
      • Gill T.P.
      • Mitchell P.
      Dairy consumption and the risk of 15-year cardiovascular disease mortality in a cohort of older Australians.
      ,
      • Bernstein A.M.
      • Pan A.
      • Rexrode K.M.
      • Stampfer M.
      • Hu F.B.
      • Mozaffarian D.
      • et al.
      Dietary protein sources and the risk of stroke in men and women.
      Sex0.44
       Male760680.91 (0.78–1.07)0.2663.80.01
      • Maruyama K.
      • Iso H.
      • Date C.
      • Kikuchi S.
      • Watanabe Y.
      • Wada Y.
      • et al.
      Dietary patterns and risk of cardiovascular deaths among middle-aged Japanese: JACC Study.
      ,
      • Kondo I.
      • Ojima T.
      • Nakamura M.
      • Hayasaka S.
      • Hozawa A.
      • Saitoh S.
      • et al.
      Consumption of dairy products and death from cardiovascular disease in the Japanese general population: the NIPPON DATA80.
      ,
      • Bernstein A.M.
      • Pan A.
      • Rexrode K.M.
      • Stampfer M.
      • Hu F.B.
      • Mozaffarian D.
      • et al.
      Dietary protein sources and the risk of stroke in men and women.
      ,
      • Goldbohm R.A.
      • Chorus A.M.
      • Galindo Garre F.
      • Schouten L.J.
      • van den Brandt P.A.
      Dairy consumption and 10-y total and cardiovascular mortality: a prospective cohort study in the Netherlands.
      ,
      • Ness A.R.
      • Smith G.D.
      • Hart C.
      Milk, coronary heart disease and mortality.
      ,
      • Larsson S.C.
      • Mannisto S.
      • Virtanen M.J.
      • Kontto J.
      • Albanes D.
      • Virtamo J.
      Dairy foods and risk of stroke.
       Female433620.86 (0.78–0.95)0.0013.60.33
      • Maruyama K.
      • Iso H.
      • Date C.
      • Kikuchi S.
      • Watanabe Y.
      • Wada Y.
      • et al.
      Dietary patterns and risk of cardiovascular deaths among middle-aged Japanese: JACC Study.
      ,
      • Kondo I.
      • Ojima T.
      • Nakamura M.
      • Hayasaka S.
      • Hozawa A.
      • Saitoh S.
      • et al.
      Consumption of dairy products and death from cardiovascular disease in the Japanese general population: the NIPPON DATA80.
      ,
      • Bernstein A.M.
      • Pan A.
      • Rexrode K.M.
      • Stampfer M.
      • Hu F.B.
      • Mozaffarian D.
      • et al.
      Dietary protein sources and the risk of stroke in men and women.
      ,
      • Goldbohm R.A.
      • Chorus A.M.
      • Galindo Garre F.
      • Schouten L.J.
      • van den Brandt P.A.
      Dairy consumption and 10-y total and cardiovascular mortality: a prospective cohort study in the Netherlands.
      Quality score0.80
       8810 6750.90 (0.85–0.95)0.960.000.00
      • Sonestedt E.
      • Wirfalt E.
      • Wallstrom P.
      • Gullberg B.
      • Orho-Melander M.
      • Hedblad B.
      Dairy products and its association with incidence of cardiovascular disease: the Malmo diet and cancer cohort.
      ,
      • Kondo I.
      • Ojima T.
      • Nakamura M.
      • Hayasaka S.
      • Hozawa A.
      • Saitoh S.
      • et al.
      Consumption of dairy products and death from cardiovascular disease in the Japanese general population: the NIPPON DATA80.
      ,
      • Bernstein A.M.
      • Pan A.
      • Rexrode K.M.
      • Stampfer M.
      • Hu F.B.
      • Mozaffarian D.
      • et al.
      Dietary protein sources and the risk of stroke in men and women.
      ,
      • Goldbohm R.A.
      • Chorus A.M.
      • Galindo Garre F.
      • Schouten L.J.
      • van den Brandt P.A.
      Dairy consumption and 10-y total and cardiovascular mortality: a prospective cohort study in the Netherlands.
      ,
      • van der Pols J.C.
      • Gunnell D.
      • Williams G.M.
      • Holly J.M.
      • Bain C.
      • Martin R.M.
      Childhood dairy and calcium intake and cardiovascular mortality in adulthood: 65-year follow-up of the Boyd Orr cohort.
      ,
      • Larsson S.C.
      • Virtamo J.
      • Wolk A.
      Dairy consumption and risk of stroke in Swedish women and men.
       6–71017 4630.86 (0.75–0.98)0.0076.70.02
      • Maruyama K.
      • Iso H.
      • Date C.
      • Kikuchi S.
      • Watanabe Y.
      • Wada Y.
      • et al.
      Dietary patterns and risk of cardiovascular deaths among middle-aged Japanese: JACC Study.
      ,
      • Dalmeijer G.W.
      • Struijk E.A.
      • van der Schouw Y.T.
      • Soedamah-Muthu S.S.
      • Verschuren W.M.
      • Boer J.M.
      • et al.
      Dairy intake and coronary heart disease or stroke – a population-based cohort study.
      ,
      • Louie J.C.
      • Flood V.M.
      • Burlutsky G.
      • Rangan A.M.
      • Gill T.P.
      • Mitchell P.
      Dairy consumption and the risk of 15-year cardiovascular disease mortality in a cohort of older Australians.
      ,
      • Elwood P.C.
      • Pickering J.E.
      • Fehily A.M.
      • Hughes J.
      • Ness A.R.
      Milk drinking, ischaemic heart disease and ischaemic stroke I. Evidence from the Caerphilly cohort.
      ,
      • Sauvaget C.
      • Nagano J.
      • Allen N.
      • Grant E.J.
      • Beral V.
      Intake of animal products and stroke mortality in the Hiroshima/Nagasaki Life Span Study.
      ,
      • Ness A.R.
      • Smith G.D.
      • Hart C.
      Milk, coronary heart disease and mortality.
      ,
      • Kinjo Y.
      • Beral V.
      • Akiba S.
      • Key T.
      • Mizuno S.
      • Appleby P.
      • et al.
      Possible protective effect of milk, meat and fish for cerebrovascular disease mortality in Japan.
      ,
      • Larsson S.C.
      • Mannisto S.
      • Virtanen M.J.
      • Kontto J.
      • Albanes D.
      • Virtamo J.
      Dairy foods and risk of stroke.
      ,
      • Lin P.H.
      • Yeh W.T.
      • Svetkey L.P.
      • Chuang S.Y.
      • Chang Y.C.
      • Wang C.
      • et al.
      Dietary intakes consistent with the DASH dietary pattern reduce blood pressure increase with age and risk for stroke in a Chinese population.
      Adjusting for 4 or more covariates (smoking, alcohol, total energy intake, BMI, physical activity and ≥3 other dietary variables)0.17
       Yes1415 3290.90 (0.84–0.97)0.0146.60.03
      • Maruyama K.
      • Iso H.
      • Date C.
      • Kikuchi S.
      • Watanabe Y.
      • Wada Y.
      • et al.
      Dietary patterns and risk of cardiovascular deaths among middle-aged Japanese: JACC Study.
      ,
      • Sonestedt E.
      • Wirfalt E.
      • Wallstrom P.
      • Gullberg B.
      • Orho-Melander M.
      • Hedblad B.
      Dairy products and its association with incidence of cardiovascular disease: the Malmo diet and cancer cohort.
      ,
      • Dalmeijer G.W.
      • Struijk E.A.
      • van der Schouw Y.T.
      • Soedamah-Muthu S.S.
      • Verschuren W.M.
      • Boer J.M.
      • et al.
      Dairy intake and coronary heart disease or stroke – a population-based cohort study.
      ,
      • Kondo I.
      • Ojima T.
      • Nakamura M.
      • Hayasaka S.
      • Hozawa A.
      • Saitoh S.
      • et al.
      Consumption of dairy products and death from cardiovascular disease in the Japanese general population: the NIPPON DATA80.
      ,
      • Louie J.C.
      • Flood V.M.
      • Burlutsky G.
      • Rangan A.M.
      • Gill T.P.
      • Mitchell P.
      Dairy consumption and the risk of 15-year cardiovascular disease mortality in a cohort of older Australians.
      ,
      • Bernstein A.M.
      • Pan A.
      • Rexrode K.M.
      • Stampfer M.
      • Hu F.B.
      • Mozaffarian D.
      • et al.
      Dietary protein sources and the risk of stroke in men and women.
      ,
      • Elwood P.C.
      • Pickering J.E.
      • Fehily A.M.
      • Hughes J.
      • Ness A.R.
      Milk drinking, ischaemic heart disease and ischaemic stroke I. Evidence from the Caerphilly cohort.
      ,
      • Goldbohm R.A.
      • Chorus A.M.
      • Galindo Garre F.
      • Schouten L.J.
      • van den Brandt P.A.
      Dairy consumption and 10-y total and cardiovascular mortality: a prospective cohort study in the Netherlands.
      ,
      • Larsson S.C.
      • Virtamo J.
      • Wolk A.
      Dairy consumption and risk of stroke in Swedish women and men.
      ,
      • Larsson S.C.
      • Mannisto S.
      • Virtanen M.J.
      • Kontto J.
      • Albanes D.
      • Virtamo J.
      Dairy foods and risk of stroke.
      ,
      • Lin P.H.
      • Yeh W.T.
      • Svetkey L.P.
      • Chuang S.Y.
      • Chang Y.C.
      • Wang C.
      • et al.
      Dietary intakes consistent with the DASH dietary pattern reduce blood pressure increase with age and risk for stroke in a Chinese population.
       No412 8090.79 (0.75–0.83)0.000.000.97
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      Stroke subtypes0.92
       Ischemic612 4390.92 (0.82–1.03)0.1463.30.02
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      Milk drinking, ischaemic heart disease and ischaemic stroke I. Evidence from the Caerphilly cohort.
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       Hemorrhagic466250.96 (0.73–1.25)0.7682.70.00
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      • Pan A.
      • Rexrode K.M.
      • Stampfer M.
      • Hu F.B.
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      • et al.
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      ,
      • Kinjo Y.
      • Beral V.
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      • et al.
      Possible protective effect of milk, meat and fish for cerebrovascular disease mortality in Japan.
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      Dairy consumption and risk of stroke in Swedish women and men.
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      Dairy foods and risk of stroke.
      Fat content of dairy0.25
       Whole-fat814 1250.96 (0.92–1.01)0.110.000.71
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      • Larsson S.C.
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      Dairy foods and risk of stroke.
       Low-fat814 1250.91 (0.85–0.97)0.0141.60.10
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      • Flood V.M.
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      • Rangan A.M.
      • Gill T.P.
      • Mitchell P.
      Dairy consumption and the risk of 15-year cardiovascular disease mortality in a cohort of older Australians.
      ,
      • Bernstein A.M.
      • Pan A.
      • Rexrode K.M.
      • Stampfer M.
      • Hu F.B.
      • Mozaffarian D.
      • et al.
      Dietary protein sources and the risk of stroke in men and women.
      ,
      • Goldbohm R.A.
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      Dairy consumption and 10-y total and cardiovascular mortality: a prospective cohort study in the Netherlands.
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      Dairy consumption and risk of stroke in Swedish women and men.
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      Dairy foods and risk of stroke.
      Specific types
       Milk1022 3820.91 (0.82–1.01)0.0874.40.000.09
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      • Wallstrom P.
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      Dairy products and its association with incidence of cardiovascular disease: the Malmo diet and cancer cohort.
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      • Hughes J.
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      Milk drinking, ischaemic heart disease and ischaemic stroke I. Evidence from the Caerphilly cohort.
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      • Holly J.M.
      • Bain C.
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      Childhood dairy and calcium intake and cardiovascular mortality in adulthood: 65-year follow-up of the Boyd Orr cohort.
      ,
      • Sauvaget C.
      • Nagano J.
      • Allen N.
      • Grant E.J.
      • Beral V.
      Intake of animal products and stroke mortality in the Hiroshima/Nagasaki Life Span Study.
      ,
      • Ness A.R.
      • Smith G.D.
      • Hart C.
      Milk, coronary heart disease and mortality.
      ,
      • Kinjo Y.
      • Beral V.
      • Akiba S.
      • Key T.
      • Mizuno S.
      • Appleby P.
      • et al.
      Possible protective effect of milk, meat and fish for cerebrovascular disease mortality in Japan.
      ,
      • Larsson S.C.
      • Virtamo J.
      • Wolk A.
      Dairy consumption and risk of stroke in Swedish women and men.
      ,
      • Larsson S.C.
      • Mannisto S.
      • Virtanen M.J.
      • Kontto J.
      • Albanes D.
      • Virtamo J.
      Dairy foods and risk of stroke.
      Fermented320180.80 (0.71–0.89)0.000.000.95
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      • Wirfalt E.
      • Wallstrom P.
      • Gullberg B.
      • Orho-Melander M.
      • Hedblad B.
      Dairy products and its association with incidence of cardiovascular disease: the Malmo diet and cancer cohort.
      ,
      • Goldbohm R.A.
      • Chorus A.M.
      • Galindo Garre F.
      • Schouten L.J.
      • van den Brandt P.A.
      Dairy consumption and 10-y total and cardiovascular mortality: a prospective cohort study in the Netherlands.
      Nonfermented320181.02 (0.89–1.17)0.810.000.63
      • Sonestedt E.
      • Wirfalt E.
      • Wallstrom P.
      • Gullberg B.
      • Orho-Melander M.
      • Hedblad B.
      Dairy products and its association with incidence of cardiovascular disease: the Malmo diet and cancer cohort.
      ,
      • Goldbohm R.A.
      • Chorus A.M.
      • Galindo Garre F.
      • Schouten L.J.
      • van den Brandt P.A.
      Dairy consumption and 10-y total and cardiovascular mortality: a prospective cohort study in the Netherlands.
       Cheese699190.94 (0.89–0.995)0.030.000.690.73
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      • Wirfalt E.
      • Wallstrom P.
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      • Hedblad B.
      Dairy products and its association with incidence of cardiovascular disease: the Malmo diet and cancer cohort.
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      • Struijk E.A.
      • van der Schouw Y.T.
      • Soedamah-Muthu S.S.
      • Verschuren W.M.
      • Boer J.M.
      • et al.
      Dairy intake and coronary heart disease or stroke – a population-based cohort study.
      ,
      • Goldbohm R.A.
      • Chorus A.M.
      • Galindo Garre F.
      • Schouten L.J.
      • van den Brandt P.A.
      Dairy consumption and 10-y total and cardiovascular mortality: a prospective cohort study in the Netherlands.
      ,
      • Larsson S.C.
      • Virtamo J.
      • Wolk A.
      Dairy consumption and risk of stroke in Swedish women and men.
      ,
      • Larsson S.C.
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      • Kontto J.
      • Albanes D.
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       Butter452990.95 (0.85–1.07)0.420.000.560.65
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      • Wirfalt E.
      • Wallstrom P.
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      Dairy products and its association with incidence of cardiovascular disease: the Malmo diet and cancer cohort.
      ,
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      Dairy consumption and 10-y total and cardiovascular mortality: a prospective cohort study in the Netherlands.
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      • Mannisto S.
      • Virtanen M.J.
      • Kontto J.
      • Albanes D.
      • Virtamo J.
      Dairy foods and risk of stroke.
       Cream385460.97 (0.88–1.06)0.440.000.400.60
      • Sonestedt E.
      • Wirfalt E.
      • Wallstrom P.
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      • Orho-Melander M.
      • Hedblad B.
      Dairy products and its association with incidence of cardiovascular disease: the Malmo diet and cancer cohort.
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      • Virtamo J.
      • Wolk A.
      Dairy consumption and risk of stroke in Swedish women and men.
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      • Larsson S.C.
      • Mannisto S.
      • Virtanen M.J.
      • Kontto J.
      • Albanes D.
      • Virtamo J.
      Dairy foods and risk of stroke.
      BMI: body mass index, REM: random effect model.
      a P value for meta-regression, and location where the study was conducted (Europe as the reference) and specific types (milk as the reference) were included as dummy variables in meta-regression.
      b N: number of results; 2 separate results (male and female) were available in 3 studies
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      .

      Total dairy

      Highest vs. lowest levels of total dairy intake were associated with risk of stroke [0.88 (0.82–0.94), I2 = 61.8%, Fig. 1]. Although no evidence of publication bias was found (P = 0.76, Supplementary Fig. 2), asymmetry in funnel plot showed ‘small-study effects’ [
      • Sterne J.A.
      • Gavaghan D.
      • Egger M.
      Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature.
      ] in 3 results [
      • Elwood P.C.
      • Pickering J.E.
      • Fehily A.M.
      • Hughes J.
      • Ness A.R.
      Milk drinking, ischaemic heart disease and ischaemic stroke I. Evidence from the Caerphilly cohort.
      ,
      • van der Pols J.C.
      • Gunnell D.
      • Williams G.M.
      • Holly J.M.
      • Bain C.
      • Martin R.M.
      Childhood dairy and calcium intake and cardiovascular mortality in adulthood: 65-year follow-up of the Boyd Orr cohort.
      ,
      • Ness A.R.
      • Smith G.D.
      • Hart C.
      Milk, coronary heart disease and mortality.
      ]. After excluding these 3 results, similar result was found [0.88 (0.82–0.95)]. Sensitivity analysis showed that the overall pooled estimate did not vary substantially with exclusion of any one study (95%CI of re-estimated effect omitting each study in turn ranged from 0.80 to 0.96, Supplementary Fig. 3); in particular, exclusion of the ATBC study including only male smokers [
      • Larsson S.C.
      • Mannisto S.
      • Virtanen M.J.
      • Kontto J.
      • Albanes D.
      • Virtamo J.
      Dairy foods and risk of stroke.
      ], which was different with that of the other studies, resulted in a pooled effect of 0.86 (0.81–0.91), and the heterogeneity dropped from 61.8% to 35.1%.
      Figure thumbnail gr1
      Figure 1The association of total dairy foods with total stroke events, stroke incidence and stroke mortality. The size of gray box is positively proportional to the weight assigned to each study, and horizontal lines represent the 95% confidence intervals.
      Meta-regression and subgroup analysis were conducted to explore potential sources of heterogeneity and perform comparison between groups. Association of total dairy intake with risk of stroke mortality [0.80 (0.76–0.84)] was stronger (P = 0.01) than incidence [0.95 (0.87–1.03)]. And the association was stronger (P < 0.00) among studies conducted in Asia [0.79 (0.75–0.82)] than Europe [0.95 (0.88–1.03)]. The effect was consistent in studies with quality score (stars) of 8 [0.90 (0.85–0.95)] and 6–7 [0.86 (0.75–0.98)] (P = 0.80), and adjustment (yes or no) for 4 or more of the following covariates (smoking, alcohol, total energy intake, BMI, physical activity and ≥3 other dietary variables) [yes: 0.90 (0.84–0.97), no: 0.79 (0.75–0.83), P = 0.17]. And the effect did not differ significantly by sex [male: 0.91 (0.78–1.07), female: 0.86 (0.78–0.95), P = 0.44], stroke subtypes [ischemic: 0.92 (0.82–1.03), hemorrhagic: 0.96 (0.73–1.25), P = 0.92], fat content of dairy [whole-fat: 0.96 (0.92–1.01), low-fat: 0.91 (0.85–0.97), P = 0.25], and specific types of dairy (milk, cheese, butter and cream) (Table 2). In addition, length of follow-up (years) (P = 0.68), year of publication (P = 0.40), mean age (P = 0.58) and number of cases (P = 0.64) were found also not significantly contributing to heterogeneity, respectively.

      Milk

      The combined RR (95%CI) of stroke for highest vs. lowest milk consumption (10 results) was 0.91 (0.82–1.01), I2 = 74.4% (Supplementary Fig. 4). Although no evidence of publication bias was found (P = 0.40, Supplementary Fig. 5), asymmetry in funnel plot showed ‘small-study effects’ [
      • Sterne J.A.
      • Gavaghan D.
      • Egger M.
      Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature.
      ] in 3 results [
      • Elwood P.C.
      • Pickering J.E.
      • Fehily A.M.
      • Hughes J.
      • Ness A.R.
      Milk drinking, ischaemic heart disease and ischaemic stroke I. Evidence from the Caerphilly cohort.
      ,
      • van der Pols J.C.
      • Gunnell D.
      • Williams G.M.
      • Holly J.M.
      • Bain C.
      • Martin R.M.
      Childhood dairy and calcium intake and cardiovascular mortality in adulthood: 65-year follow-up of the Boyd Orr cohort.
      ,
      • Ness A.R.
      • Smith G.D.
      • Hart C.
      Milk, coronary heart disease and mortality.
      ]. After excluding these 3 results, similar result was found: 0.92 (0.82–1.02). Sensitivity analysis omitting 1 study in turn showed that the ATBC study [
      • Larsson S.C.
      • Mannisto S.
      • Virtanen M.J.
      • Kontto J.
      • Albanes D.
      • Virtamo J.
      Dairy foods and risk of stroke.
      ] was excessively influential because its “omitted” meta-analytic estimate [0.86 (0.81–0.92)] differs in significance relative to the overall analysis, and the heterogeneity dropped from 74.4% to 27.9%. The association remained not significant excluding each of the other studies in turn (Supplementary Fig. 6).
      Excluding 2 studies [
      • Sonestedt E.
      • Wirfalt E.
      • Wallstrom P.
      • Gullberg B.
      • Orho-Melander M.
      • Hedblad B.
      Dairy products and its association with incidence of cardiovascular disease: the Malmo diet and cancer cohort.
      ,
      • Goldbohm R.A.
      • Chorus A.M.
      • Galindo Garre F.
      • Schouten L.J.
      • van den Brandt P.A.
      Dairy consumption and 10-y total and cardiovascular mortality: a prospective cohort study in the Netherlands.
      ] in which milk products were also included showed similar result [0.91 (0.78–1.05)] among the others having milk specifically. Larsson et al. [
      • Larsson S.C.
      • Mannisto S.
      • Virtanen M.J.
      • Kontto J.
      • Albanes D.
      • Virtamo J.
      Dairy foods and risk of stroke.
      ] presented result of whole-fat and low-fat milk separately, and separated meta-analysis showed significant association when including the result of low-fat milk only [0.90 (0.83–0.98)] but not whole-fat milk only [0.91 (0.83–1.01)].
      The effect did not differ significantly by outcome [stroke incidence: 0.91 (0.80–1.04); stroke mortality: 0.92 (0.79–1.06)] (P = 0.98), location [Europe: 0.96 (0.89–1.03); Asia: 0.84 (0.72–0.996)] (P = 0.32), quality score [8 stars: 0.91 (0.84–0.98); 6–7 stars: 0.91 (0.74–1.12)] (P = 0.64), and adjustment for 4 or more of the above-mentioned covariates [yes: 0.95 (0.87–1.04); no: 0.82 (0.75–0.90)] (P = 0.35). In addition, length of follow-up (years) (P = 0.33), year of publication (P = 0.35), mean age (P = 0.37) and number of cases (P = 0.19) were found also not significantly contributing to heterogeneity, respectively. The association of fermented milk and nonfermented milk with risk of total stroke events was 0.80 (0.71–0.89) and 1.02 (0.89–1.17), but the difference was not significant (P = 0.09).
      For dose–response analysis, dairy milk was estimated to be on average 200 ml for each serving [
      • Soedamah-Muthu S.S.
      • Ding E.L.
      • Al-Delaimy W.K.
      • Hu F.B.
      • Engberink M.F.
      • Willett W.C.
      • et al.
      Milk and dairy consumption and incidence of cardiovascular diseases and all-cause mortality: dose-response meta-analysis of prospective cohort studies.
      ]. Data from 6 studies [
      • Elwood P.C.
      • Pickering J.E.
      • Fehily A.M.
      • Hughes J.
      • Ness A.R.
      Milk drinking, ischaemic heart disease and ischaemic stroke I. Evidence from the Caerphilly cohort.
      ,
      • van der Pols J.C.
      • Gunnell D.
      • Williams G.M.
      • Holly J.M.
      • Bain C.
      • Martin R.M.
      Childhood dairy and calcium intake and cardiovascular mortality in adulthood: 65-year follow-up of the Boyd Orr cohort.
      ,
      • Sauvaget C.
      • Nagano J.
      • Allen N.
      • Grant E.J.
      • Beral V.
      Intake of animal products and stroke mortality in the Hiroshima/Nagasaki Life Span Study.
      ,
      • Ness A.R.
      • Smith G.D.
      • Hart C.
      Milk, coronary heart disease and mortality.
      ,
      • Kinjo Y.
      • Beral V.
      • Akiba S.
      • Key T.
      • Mizuno S.
      • Appleby P.
      • et al.
      Possible protective effect of milk, meat and fish for cerebrovascular disease mortality in Japan.
      ,
      • Larsson S.C.
      • Virtamo J.
      • Wolk A.
      Dairy consumption and risk of stroke in Swedish women and men.
      ] including 16 715 stroke cases were included. A non-linear relationship (P = 2.80*10−13) was found, and protection of milk on total stroke events reach maximum at about 200 ml/day. The risk of total stroke events was 0.88 (0.86–0.91), 0.82 (0.79–0.86), 0.83 (0.79–0.86), 0.85 (0.81–0.89), 0.86 (0.82–0.91), 0.91 (0.84–0.98) and 0.94 (0.86–1.02) for 100, 200, 300, 400, 500, 600 and 700 ml/day of milk, respectively (Fig. 2). Excluding 2 studies [
      • Elwood P.C.
      • Pickering J.E.
      • Fehily A.M.
      • Hughes J.
      • Ness A.R.
      Milk drinking, ischaemic heart disease and ischaemic stroke I. Evidence from the Caerphilly cohort.
      ,
      • Larsson S.C.
      • Virtamo J.
      • Wolk A.
      Dairy consumption and risk of stroke in Swedish women and men.
      ] with stroke incidence, the non-linear relationship (P = 2.55*10−4) was also found, and the protection of milk on stroke mortality reach maximum at about 200 ml/day [0.80 (0.77–0.84)].
      Figure thumbnail gr2
      Figure 2The dose–response analysis between milk consumption and total stroke events. The solid line and the long dash line represent the estimated relative risk and its 95% confidence interval.

      Cheese, butter and cream (Supplementary Fig. 4)

      Highest vs. lowest cheese consumption (6 results) conferred an RR (95%CI) of 0.94 (0.89–0.995), I2 = 0.00%. Butter [0.95 (0.85–1.07), I2 = 0.00%, 4 results] and cream [0.97 (0.88–1.06), I2 = 0.00%, 3 results] was not associated with risk of stroke. No evidence of publication bias was found for cheese (P = 0.62), butter (P = 0.88) and cream (P = 0.30). Sensitivity analysis showed that the pooled estimate did not vary substantially with exclusion of any one study for cheese, butter and cream, respectively.

      Discussion

      Findings from this meta-analysis indicated that total dairy foods might be inversely associated with risk of stroke events, and the inverse association might be attributable to low-fat dairy foods, milk (especially for fermented milk) and cheese. A non-linear relationship was found between milk consumption and risk of stroke, with the strongest association (18% lower risk) being observed at about 200 ml/day, and direction of protection was still observed at 700 ml/day [0.94 (0.86–1.02)].
      Several biological mechanisms for the observed association have been proposed. First, the inverse association might be mediated through reduction in blood pressure. A recent meta-analysis showed that the risk of hypertension per 200 g/day was 0.97 (0.95–0.99) for total dairy, 0.96 (0.93–0.99) for low-fat dairy, and 0.96 (0.94–0.98) for milk, but high-fat dairy, total fermented dairy, yogurt and cheese were not significantly associated with hypertension incidence [
      • Soedamah-Muthu S.S.
      • Verberne L.D.
      • Ding E.L.
      • Engberink M.F.
      • Geleijnse J.M.
      Dairy consumption and incidence of hypertension: a dose-response meta-analysis of prospective cohort studies.
      ]. Randomized controlled trials (RCT) suggested that tripeptides, originating from milk fermentation, could reduce blood pressure [
      • Xu J.Y.
      • Qin L.Q.
      • Wang P.Y.
      • Li W.
      • Chang C.
      Effect of milk tripeptides on blood pressure: a meta-analysis of randomized controlled trials.
      ]. Result from an RCT also indicated that milk protein supplementation was significantly associated with −2.3 mmHg net changes in systolic blood pressure [
      • He J.
      • Wofford M.R.
      • Reynolds K.
      • Chen J.
      • Chen C.S.
      • Myers L.
      • et al.
      Effect of dietary protein supplementation on blood pressure: a randomized, controlled trial.
      ]. Second, dairy products are important contributors to saturated fatty acids, which are considered to have negative effect on cardiovascular disease due to their low-density lipoprotein cholesterol raising effect. However, a recent meta-analysis found no association between saturated fat intake and coronary heart disease [1.07 (0.96–1.19)], stroke [0.81 (0.62–1.05)], and cardiovascular disease [CVD, 1.00 (0.89–1.11)] [
      • Siri-Tarino P.W.
      • Sun Q.
      • Hu F.B.
      • Krauss R.M.
      Meta-analysis of prospective cohort studies evaluating the association of saturated fat with cardiovascular disease.
      ]. Furthermore, dairy or milk fat intake was inversely related to the risk of a first event of stroke [
      • Warensjo E.
      • Smedman A.
      • Stegmayr B.
      • Hallmans G.
      • Weinehall L.
      • Vessby B.
      • et al.
      Stroke and plasma markers of milk fat intake – a prospective nested case-control study.
      ]. These findings might partially explain the inverse but not significant association between whole/high-fat dairy foods and stroke events. Other possible mechanisms might involve the protection of potassium [
      • Larsson S.C.
      • Orsini N.
      • Wolk A.
      Dietary potassium intake and risk of stroke: a dose-response meta-analysis of prospective studies.
      ], magnesium [
      • Larsson S.C.
      • Orsini N.
      • Wolk A.
      Dietary magnesium intake and risk of stroke: a meta-analysis of prospective studies.
      ], calcium [
      • Larsson S.C.
      • Orsini N.
      • Wolk A.
      Dietary calcium intake and risk of stroke: a dose-response meta-analysis.
      ] in dairy foods [
      • Larsson S.C.
      • Virtamo J.
      • Wolk A.
      Dairy consumption and risk of stroke in Swedish women and men.
      ] on stroke events, significant association of fermented dairy foods with lower HOMA index and lower LDL-C levels [
      • Sonestedt E.
      • Wirfalt E.
      • Wallstrom P.
      • Gullberg B.
      • Orho-Melander M.
      • Hedblad B.
      Dairy products and its association with incidence of cardiovascular disease: the Malmo diet and cancer cohort.
      ,
      • Agerholm-Larsen L.
      • Bell M.L.
      • Grunwald G.K.
      • Astrup A.
      The effect of a probiotic milk product on plasma cholesterol: a meta-analysis of short-term intervention studies.
      ], favorable effect of probiotic bacteria found in fermented milk on metabolic disorders [
      • Cani P.D.
      • Delzenne N.M.
      The role of the gut microbiota in energy metabolism and metabolic disease.
      ], and favorable effect of cheese on blood lipids and cholesterol relative to butter [
      • Biong A.S.
      • Muller H.
      • Seljeflot I.
      • Veierod M.B.
      • Pedersen J.I.
      A comparison of the effects of cheese and butter on serum lipids, haemostatic variables and homocysteine.
      ]. In addition, consumption of low-fat dairy foods was found to be an important predictor of serum 25-hydroxyvitamin D levels during winter among women [
      • Burgaz A.
      • Akesson A.
      • Oster A.
      • Michaelsson K.
      • Wolk A.
      Associations of diet, supplement use, and ultraviolet B radiation exposure with vitamin D status in Swedish women during winter.
      ], which was found linearly associated with reduced risk of hypertension [
      • Wu Y.
      • Li S.
      • Zhang D.
      Circulating 25-hydroxyvitamin D levels and hypertension risk.
      ].
      A previous meta-analysis [
      • Soedamah-Muthu S.S.
      • Ding E.L.
      • Al-Delaimy W.K.
      • Hu F.B.
      • Engberink M.F.
      • Willett W.C.
      • et al.
      Milk and dairy consumption and incidence of cardiovascular diseases and all-cause mortality: dose-response meta-analysis of prospective cohort studies.
      ] found that per 200 ml/day of dairy (mainly milk) was inversely but not significantly associated with stroke [0.87 (0.72–1.07), 6 prospective cohort studies] when assuming a linear relationship, and result from the Nurses' Health Study [
      • Iso H.
      • Stampfer M.J.
      • Manson J.E.
      • Rexrode K.
      • Hennekens C.H.
      • Colditz G.A.
      • et al.
      Prospective study of calcium, potassium, and magnesium intake and risk of stroke in women.
      ] was also updated by Bernstein et al. [
      • Bernstein A.M.
      • Pan A.
      • Rexrode K.M.
      • Stampfer M.
      • Hu F.B.
      • Mozaffarian D.
      • et al.
      Dietary protein sources and the risk of stroke in men and women.
      ]. However, the association of dairy foods with risk of stroke by stroke events (incidence and mortality), location, sex and specific types of dairy foods are still not summarized. In addition, the dose–response relationship of dairy foods with risk of stroke was still unknown. Our meta-analysis, with almost twice the number of stroke cases and subgroup analysis, should provide a better understanding regarding dairy foods and risk of stroke. However, other limitations should be considered.
      First, moderate between-study heterogeneity was found. Sensitivity analysis found that the heterogeneity was caused mainly by result from the Finnish male smokers [
      • Larsson S.C.
      • Mannisto S.
      • Virtanen M.J.
      • Kontto J.
      • Albanes D.
      • Virtamo J.
      Dairy foods and risk of stroke.
      ]. Besides the older subjects and the very narrow and quite high average intake of dairy foods, the fact that only smokers involved might also contribute to the discrepancy, because smoking is an established risk factor of stroke [
      • Peters S.A.
      • Huxley R.R.
      • Woodward M.
      Smoking as a risk factor for stroke in women Compared with men: a systematic review and meta-analysis of 81 cohorts, including 3 980 359 individuals and 42 401 strokes.
      ]. Thus the effect of dairy foods on risk of stroke among smokers deserves further investigation. Second, the results for ischemic and hemorrhagic stroke should be interpreted cautiously, because of small number of results. Among the 6 studies included for ischemic stroke, inverse association (significant in 1, non-significant in 4) was found in 5 studies, while results from ATBC study [
      • Larsson S.C.
      • Mannisto S.
      • Virtanen M.J.
      • Kontto J.
      • Albanes D.
      • Virtamo J.
      Dairy foods and risk of stroke.
      ] indicated a positive effect [1.14 (0.99–1.32)]. Among the 4 studies for hemorrhagic stroke, significantly inverse association was found in 1 study [
      • Kinjo Y.
      • Beral V.
      • Akiba S.
      • Key T.
      • Mizuno S.
      • Appleby P.
      • et al.
      Possible protective effect of milk, meat and fish for cerebrovascular disease mortality in Japan.
      ], while results from the ATBC study [
      • Larsson S.C.
      • Mannisto S.
      • Virtanen M.J.
      • Kontto J.
      • Albanes D.
      • Virtamo J.
      Dairy foods and risk of stroke.
      ] indicated a positive effect [1.33 (0.97–1.82)], and no association was found in the other 2 studies. Beneficial effects of fermented dairy on cholesterol concentrations and metabolism were found [
      • St-Onge M.P.
      • Farnworth E.R.
      • Jones P.J.
      Consumption of fermented and nonfermented dairy products: effects on cholesterol concentrations and metabolism.
      ], and cheese was found inversely associated with risk of stroke. Yogurt, another commonly consumed fermented dairy, was found significantly associated with reduced risk of stroke in both male and female in Netherlands Cohort Study [
      • Goldbohm R.A.
      • Chorus A.M.
      • Galindo Garre F.
      • Schouten L.J.
      • van den Brandt P.A.
      Dairy consumption and 10-y total and cardiovascular mortality: a prospective cohort study in the Netherlands.
      ] but not in ATBC study [
      • Larsson S.C.
      • Mannisto S.
      • Virtanen M.J.
      • Kontto J.
      • Albanes D.
      • Virtamo J.
      Dairy foods and risk of stroke.
      ]. While the study by Sonestedt et al. showed a reduced risk of stroke with low-fat but not high-fat milk [
      • Sonestedt E.
      • Wirfalt E.
      • Wallstrom P.
      • Gullberg B.
      • Orho-Melander M.
      • Hedblad B.
      Dairy products and its association with incidence of cardiovascular disease: the Malmo diet and cancer cohort.
      ], no association was found for both low-fat and high-fat milk in ATBC study [
      • Larsson S.C.
      • Mannisto S.
      • Virtanen M.J.
      • Kontto J.
      • Albanes D.
      • Virtamo J.
      Dairy foods and risk of stroke.
      ], and no association was found for both low-fat and high-fat milk (fermented or not) [
      • Goldbohm R.A.
      • Chorus A.M.
      • Galindo Garre F.
      • Schouten L.J.
      • van den Brandt P.A.
      Dairy consumption and 10-y total and cardiovascular mortality: a prospective cohort study in the Netherlands.
      ]. Low-fat and high-fat cheese was not significantly associated with risk of stroke [
      • Goldbohm R.A.
      • Chorus A.M.
      • Galindo Garre F.
      • Schouten L.J.
      • van den Brandt P.A.
      Dairy consumption and 10-y total and cardiovascular mortality: a prospective cohort study in the Netherlands.
      ], respectively. However, the limited data precluded a robust assessment of above-mentioned findings. In addition, results on the effect of cheese, milk, butter and cream were also based on limited data, which need to be confirmed.
      Third, factors that might influence the effect estimation should be noteworthy. Presumably, participants, especially for individuals with high risk of developing CVD may have changed dairy food consumption during follow-up, but the proportion of men with a vascular event who had changed to fat-reduced milk was no different to that in men who had no vascular event in Caerphilly cohort [
      • Elwood P.C.
      • Pickering J.E.
      • Fehily A.M.
      • Hughes J.
      • Ness A.R.
      Milk drinking, ischaemic heart disease and ischaemic stroke I. Evidence from the Caerphilly cohort.
      ], and similar results were found after excluding those with suspected unstable food habits [
      • Sonestedt E.
      • Wirfalt E.
      • Wallstrom P.
      • Gullberg B.
      • Orho-Melander M.
      • Hedblad B.
      Dairy products and its association with incidence of cardiovascular disease: the Malmo diet and cancer cohort.
      ,
      • Dalmeijer G.W.
      • Struijk E.A.
      • van der Schouw Y.T.
      • Soedamah-Muthu S.S.
      • Verschuren W.M.
      • Boer J.M.
      • et al.
      Dairy intake and coronary heart disease or stroke – a population-based cohort study.
      ]. Although we extracted RRs that adjusted for the most confounders, the extent to which they were adjusted and the possibility that the observed association was due to unmeasured or residual confounding should be considered. Fourth, a U-shaped association was found between cheese consumption and CVD risk among men by Sonestedt et al. [
      • Sonestedt E.
      • Wirfalt E.
      • Wallstrom P.
      • Gullberg B.
      • Orho-Melander M.
      • Hedblad B.
      Dairy products and its association with incidence of cardiovascular disease: the Malmo diet and cancer cohort.
      ] However, dose–response relationship was only conducted for milk in this meta-analysis, thus suggestions on amount of dairy foods, cheese and low-fat dairy foods deserve to be explored in further studies. Finally, although no significant publication bias was detected, validity of publication bias test should be questioned because of small number of studies included [
      • Sterne J.A.
      • Gavaghan D.
      • Egger M.
      Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature.
      ]. In addition, ‘small-study effect’ [
      • Sterne J.A.
      • Gavaghan D.
      • Egger M.
      Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature.
      ] was detected in funnel plot, however, similar results were found after excluding the 3 results [
      • Elwood P.C.
      • Pickering J.E.
      • Fehily A.M.
      • Hughes J.
      • Ness A.R.
      Milk drinking, ischaemic heart disease and ischaemic stroke I. Evidence from the Caerphilly cohort.
      ,
      • van der Pols J.C.
      • Gunnell D.
      • Williams G.M.
      • Holly J.M.
      • Bain C.
      • Martin R.M.
      Childhood dairy and calcium intake and cardiovascular mortality in adulthood: 65-year follow-up of the Boyd Orr cohort.
      ,
      • Ness A.R.
      • Smith G.D.
      • Hart C.
      Milk, coronary heart disease and mortality.
      ] leading to ‘small-study effect’.
      With regard to dietary protein sources, significantly reduced risk of stroke associated with substitution of red meat with either of whole-fat dairy or low-fat dairy foods was found in Nurses' Health Study [
      • Bernstein A.M.
      • Pan A.
      • Rexrode K.M.
      • Stampfer M.
      • Hu F.B.
      • Mozaffarian D.
      • et al.
      Dietary protein sources and the risk of stroke in men and women.
      ], and benefit on risk of stroke substituting sugar-sweetened beverages with dairy was anticipated given the enhanced cardiometabolic risk after higher intake of sugar-sweetened beverages [
      • Richelsen B.
      Sugar-sweetened beverages and cardio-metabolic disease risks.
      ]. However, there seems no need to substitute dairy for tea and coffee, which were also inversely associated with risk of stroke [
      • Larsson S.C.
      • Orsini N.
      Coffee consumption and risk of stroke: a dose-response meta-analysis of prospective studies.
      ,
      • Arab L.
      • Liu W.
      • Elashoff D.
      Green and black tea consumption and risk of stroke: a meta-analysis.
      ].
      In summary, dairy foods, especially for low-fat dairy, milk and cheese, might be associated with reduced risk of stroke. Future studies are needed to examine the risk for ischemic and hemorrhagic strokes separately, and clarify the dose–response relationship.

      Conflict of interest

      None.

      Acknowledgments

      None.

      Appendix A. Supplementary data

      The following is the supplementary data related to this article:

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