Milk intake and incident stroke and CHD in populations of European descent: a Mendelian randomisation study

We thank all EPIC participants and staff for their contribution to the study. We also thank staff from the EPIC-CVD coordinating centres for sample preparation and data handling. This research has been conducted using the UK Biobank Resource (application number 29916). Data on coronary artery disease have been contributed by CARDIoGRAMplusC4D investigators and have been downloaded from www.CARDIOGRAMPLUSC4D.ORG.I Sluijswas supported by a personal Dr. Dekker postdoctoral grant (2015T019) from the Netherlands Heart Foundation. NGF and FI acknowledge core Medical Research Council Epidemiology Unit support (MC_UU_12015/5) and NGF acknowledges NIHR Biomedical Research Centre Cambridge: Nutrition, Diet, and Lifestyle Research Theme (IS-BRC-1215-20014). The InterAct project was funded by the EU FP6 programme (grant number LSHM_CT_2006_037197) and provided the biomarker data in the sub-cohort that was used in the current study. These analyses were supported by Cancer Research UK (C8221/A19170). The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); Health Research Fund (FIS) PI13/00061 (EPIC-Granada) and PI13/01162 (EPIC-Murcia), Regional Governments of Andalucia, Asturias, Basque Country, Murcia and Navarra, ISCIII Health Research Funds RD12/0036/0018 (cofounded by FEDER funds/European Regional Development Fund ERDF) (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skane and Vasterbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 for EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (UK). EPIC-CVD has been supported by the European Commission Framework Programme 7 (HEALTH-F2-2012-279233), the European Research Council (268834), the UK Medical Research Council (MR/L003120/1), the British Heart Foundation (RG13/13/30194 and RG/18/13/33946) and the National Institute for Health Research (Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust). The MEGASTROKE project received funding from sources specified at http://www.megastroke.org/acknowledgments.html. L.E.T.V.analysed the data and drafted the manuscript. L. E. T. V., I. S. and Y. T. vdS. had access to all data for this study. L. E. T. V., I. S., Y. T. vdS., S. B., N. G. F., H. F., F. I., T. K. N., F. R., E. W., K. A., C. D., A. P. C., M. B. S., T. Y. N. T. and A. S. B. contributed to study conception, design and interpretation of data. All authors contributed to critical revision of the manuscript and approval of version to be published.Higher milk intake has been associated with a lower stroke risk, but not with risk of CHD. Residual confounding or reverse causation cannot be excluded. Therefore, we estimated the causal association of milk consumption with stroke and CHD risk through instrumental variable (IV) and gene-outcome analyses. IV analysis included 29 328 participants (4611 stroke; 9828 CHD) of the European Prospective Investigation into Cancer and Nutrition (EPIC)-CVD (eight European countries) and European Prospective Investigation into Cancer and Nutrition-Netherlands (EPIC-NL) case-cohort studies. rs4988235, a lactase persistence (LP) SNP which enables digestion of lactose in adulthood was used as genetic instrument. Intake of milk was first regressed on rs4988235 in a linear regression model. Next, associations of genetically predicted milk consumption with stroke and CHD were estimated using Prentice-weighted Cox regression. Gene-outcome analysis included 777 024 participants (50 804 cases) from MEGASTROKE (including EPIC-CVD), UK Biobank and EPIC-NL for stroke, and 483 966 participants (61 612 cases) from CARDIoGRAM, UK Biobank, EPIC-CVD and EPIC-NL for CHD. In IV analyses, each additional LP allele was associated with a higher intake of milk in EPIC-CVD (beta = 13 center dot 7 g/d; 95 % CI 8 center dot 4, 19 center dot 1) and EPIC-NL (36 center dot 8 g/d; 95 % CI 20 center dot 0, 53 center dot 5). Genetically predicted milk intake was not associated with stroke (HR per 25 g/d 1 center dot 05; 95 % CI 0 center dot 94, 1 center dot 16) or CHD (1 center dot 02; 95 % CI 0 center dot 96, 1 center dot 08). In gene-outcome analyses, there was no association of rs4988235 with risk of stroke (OR 1 center dot 02; 95 % CI 0 center dot 99, 1 center dot 05) or CHD (OR 0 center dot 99; 95 % CI 0 center dot 95, 1 center dot 03). Current Mendelian randomisation analysis does not provide evidence for a causal inverse relationship between milk consumption and stroke or CHD risk.Netherlands Heart Foundation 2015T019UK Research & Innovation (UKRI) Medical Research Council UK (MRC)European Commission MC_UU_12015/5NIHR Biomedical Research Centre Cambridge: Nutrition, Diet, and Lifestyle Research Theme IS-BRC-1215-20014European Commission LSHM_CT_2006_037197Cancer Research UK C8221/A19170European Commission European Commission Joint Research CentreInternational Agency for Research on CancerDanish Cancer SocietyDeutsche Krebshilfe German Cancer Research Center (DKFZ) (Germany)Federal Ministry of Education & Research (BMBF)Deutsche Krebshilfe Deutsches Krebsforschungszentrum (Germany)Federal Ministry of Education & Research (BMBF)Fondazione AIRC per la ricerca sul cancro Consiglio Nazionale delle Ricerche (CNR)Netherlands Government Netherlands GovernmentWorld Cancer Research Fund International (WCRF)Netherlands GovernmentInstituto de Salud Carlos III PI13/00061 PI13/01162Junta de Andalucia Regional Government of Asturias (Spain) Regional Government of Basque Country (Spain) Regional Government of Murcia (Spain) Regional Government of Navarra (Spain)ISCIII Health Research Funds (FEDER funds/European Regional Development Fund ERDF) (Spain) RD12/0036/0018Swedish Cancer Society Swedish Research Council County Council of Skane (Sweden) County Council of Vasterbotten (Sweden)European Commission Framework Programme 7 HEALTH-F2-2012-279233 European Research Council (ERC) European Commission 268834UK Research & Innovation (UKRI) Medical Research Council UK (MRC) MR/L003120/1 British Heart Foundation RG13/13/30194 RG/18/13/33946 National Institute for Health Research (Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust) UK Research & Innovation (UKRI) Medical Research Council UK (MRC) 1000143 MR/M012190/1 Cancer Research UK C8221/A19170 14136 C570/A1649