Dairy consumption, systolic blood pressure, and risk of hypertension: Mendelian randomization study

Authors: DING, MING - Harvard University; HUANG, TAO - Harvard University; BERGHOLDT, HELLE - University Of Copenhagen; FRAZIER WOOD, ALEXIS - Baylor College Of Medicine; ASLIBEKYAN, STELLA - University Of Alabama; NORTH, KARI - University Of North Carolina; VOORTMAN, TRUDY - University Medical Center Utrecht; GRAFF, MARIAELISA - University Of North Carolina; SMITH, CAREN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; Lai, Chao Qiang; VARBO, ANETTE - University Of Copenhagen; LEMAITRE, ROZENN - University Of Washington; DE JONGE, ESTER - University Medical Center Utrecht; FUMERON, FREDERIC - Centre De Recherche Sur Les Macromolécules Végétales (CERMAV); CORELLA, DOLORES - University Of Valencia; WANG, CAROL - University Of Western Australia; TJONNELAND, ANNE - Danish Cancer Society Research Center; OVERVAD, KIM - Aarhus University; SORENSEN, THORKILD - University Of Copenhagen; FEITOSA, MARY - Washington University; WOJCZYNSKI, MARY - Washington University; KAHONEN, MIKA - University Of Tampere; AHMAD, SHAFQAT - Lund University; TRNDYTOM, FRIDA - Lund University; PSATY, BRUCE - University Of Washington; SISCOVICK, DAVID - New York Academy Of Medicine; BARROSO, INES - Wellcome Trust Sanger Institute; JOHANSSON, INGEGERD - University Of Umea; HERNANDEZ, DENA - National Institutes Of Health (NIH); FERRUCCI, LUIGI - National Institutes Of Health (NIH); BANDINELLI, STEFANIA - Tuscany Regional Health Agency; LINNEBERG, ALLAN - Research Centre For Prevention And Health; SANDHOLT, CAMILLA - University Of Copenhagen; PEDERSEN, OLUF - University Of Copenhagen; HANSEN, TORBEN - University Of Copenhagen; SCHULZ, CHRISTINA - Lund University; SONESTEDT, EMILY - Lund University; ORHO-MELANDER, MARJU - Lund University; CHEN, TZU-AN - Baylor College Of Medicine; ROTTER, JEROME - Los Angeles Biomedical Research Institute; ALLISON, MATHEW - University Of California; RICH, STEPHEN - University Of Virginia; SORLI, JOSE - University Of Valencia; COLTELL, OSCAR - University Jaume I Of Castellon; PENNELL, CRAIG - University Of Western Australia; EASTWOOD, PETER - University Of Western Australia; HOFMAN, ALBERT - University Medical Center Utrecht; UITTERLINDEN, ANDRE - University Medical Center Utrecht; ZILLIKENS, M. CAROLA - University Medical Center Utrecht; VAN ROOIJ, FRANK - University Medical Center Utrecht; CHU, AUDREY - Harvard University; ROSE, LYNDA - Harvard University; RIDKER, PAUL - Harvard University; VIIKARI, JORMA - University Of Turku; RAITAKARA, OLLI - University Of Turku; LEHTIMAKI, TERHO - University Of Tampere; MIKKILA, VERA - University Of Helsinki; WILLETT, WALTER - Harvard University; WANG, YUJIE - University Of North Carolina; TUCKER, KATHERINE - University Of Massachusetts; ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; KILPELAINEN, TUOMAS - University Of Copenhagen; PROVINCE, MICHAEL - Washington University; FRANKS, PAUL - Lund University; ARNETT, DONNA - University Of Alabama; TANAKA, TOSHIKO - National Institutes Of Health (NIH); TOFT, ULLA - Research Centre For Prevention And Health; ERICSON, ULRIKA - Lund University; FRANCO, OSCAR - University Medical Center Utrecht; MOZAFFARIAN, DARIUSH - Tufts University; HU, FRANK - Harvard University; CHASMAN, DANIEL - Harvard University; NORDESTGAARD, BORGE - University Of Copenhagen; ELLERVIK, CHRISTINA - Boston Children'S Hospital; QI, LU - Harvard University

Submitted to: British Medical Journal
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/27/2017
Publication Date: 3/16/2017
Citation: Ding, M., Huang, T., Bergholdt, H.K., Frazier Wood, A.C., Aslibekyan, S., North, K.E., Voortman, T., Graff, M., Smith, C.E., Lai, C., Varbo, A., Lemaitre, R.N., De Jonge, E.A., Fumeron, F., Corella, D., Wang, C.A., Tjonneland, A., Overvad, K., Sorensen, T.I., Feitosa, M.F., Wojczynski, M.K., Kahonen, M., Ahmad, S., Trndytom, F., Psaty, B.M., Siscovick, D.S., Barroso, I., Johansson, I., Hernandez, D.G., Ferrucci, L., Bandinelli, S., Linneberg, A., Sandholt, C.H., Pedersen, O., Hansen, T., Schulz, C., Sonestedt, E., Orho-Melander, M., Chen, T., Rotter, J.I., Allison, M.A., Rich, S.S., Sorli, J.V., Coltell, O., Pennell, C.E., Eastwood, P., Hofman, A., Uitterlinden, A.G., Zillikens, M., Van Rooij, F.J., Chu, A.Y., Rose, L.M., Ridker, P.M., Viikari, J., Raitakara, O., Lehtimaki, T., Mikkila, V., Willett, W.C., Wang, Y., Tucker, K.L., Ordovas, J.M., Kilpelainen, T.O., Province, M.A., Franks, P.W., Arnett, D.K., Tanaka, T., Toft, U., Ericson, U., Franco, O.H., Mozaffarian, D., Hu, F.B., Chasman, D.I., Nordestgaard, B.G., Ellervik, C., Qi, L. 2017. Dairy consumption, systolic blood pressure, and risk of hypertension: Mendelian randomization study. British Medical Journal. doi: 10.1136/bmj.j1000.

Interpretive Summary: Previous studies have reported that the intake of dairy foods lowers blood pressure and reduces hypertension. These studies relied on questionnaires to estimate dairy consumption, and the information collected through these methods may be imprecise. However, other methods of estimating dairy consumption may be more accurate. For example, dairy food estimates may be amenable to approaches that use genetics. One of these genetic approaches is called Mendelian randomization, and for dairy foods, Mendelian Randomization relies on a mutation in a single gene called lactase. The lactase mutation determines who is lactose-tolerant and can easily consume dairy foods. This allows us to use the presence of the mutation to represent dairy intake. The current study used Mendelian randomization to investigate relationships among the lactase gene mutation, the consumption of dairy foods, and blood pressure in over 197,000 people. This large-scale study began by combining results from 22 cross-sectional (one point in time) studies from around the world. In order to strengthen their results, the authors analyzed 10 additional "prospective studies" (carried out in 26,000 people) and 8 clinical trials. Prospective studies provide a higher level of evidence than cross-sectional studies because they look at changes in blood pressure over time. Clinical trials show the "before and after" effects of giving people dairy foods and are considered the highest level of evidence. Conclusions from these different types of studies were mixed. The lactase genetic mutations were associated with greater dairy intake, as the authors expected. However, the mutation was not associated with lower blood pressure or less hypertension. These findings may suggest that reliance on a single food group (like dairy foods) to address a complex disease (like hypertension) may not be the most effective approach. Instead we may need to study the overall dietary pattern and its connection to age-related diseases.

Technical Abstract: Objective: To examine whether previous observed inverse associations of dairy intake with systolic blood pressure and risk of hypertension were causal. Design: Mendelian randomization study using the single nucleotide polymorphism rs4988235 related to lactase persistence as an instrumental variable. Setting: CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium. Participants: Data from 22 studies with 171,213 participants, and an additional 10 published prospective studies with 26,119 participants included in the observational analysis. Main Outcome Measures: The instrumental variable estimation was conducted using the ratio of coefficients approach. Using meta-analysis, an additional eight published randomized clinical trials on the association of dairy consumption with systolic blood pressure were summarized. Results: Compared with the CC genotype (CC is associated with complete lactase deficiency), the CT/TT genotype (TT is associated with lactose persistence, and CT is associated with certain lactase deficiency) of LCT-13910 (lactase persistence gene) rs4988235 was associated with higher dairy consumption (0.23 (about 55 g/day), 95% confidence interval 0.17 to 0.29) serving/day; P<0.001) and was not associated with systolic blood pressure (0.31, 95% confidence interval -0.05 to 0.68 mm Hg; P=0.09) or risk of hypertension (odds ratio 1.01, 95% confidence interval 0.97 to 1.05; P=0.27). Using LCT-13910 rs4988235 as the instrumental variable, genetically determined dairy consumption was not associated with systolic blood pressure (beta=1.35, 95% confidence interval -0.28 to 2.97 mm Hg for each serving/day) or risk of hypertension (odds ratio 1.04, 0.88 to 1.24). Moreover, meta-analysis of the published clinical trials showed that higher dairy intake has no significant effect on change in systolic blood pressure for interventions over one month to 12 months (intervention compared with control groups: beta=-0.21, 95% confidence interval -0.98 to 0.57 mm Hg). In observational analysis, each serving/day increase in dairy consumption was associated with -0.11 (95% confidence interval -0.20 to -0.02 mm Hg; P=0.02) lower systolic blood pressure but not risk of hypertension (odds ratio 0.98, 0.97 to 1.00; P=0.11). Conclusion: The weak inverse association between dairy intake and systolic blood pressure in observational studies was not supported by a comprehensive instrumental variable analysis and systematic review of existing clinical trials.