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Lactase persistence, milk intake, and mortality in the Danish general population: a Mendelian randomization study

Abstract

Meta-analyses have suggested no association between milk intake and mortality. Since only few studies have been conducted, we investigated the association between the lactase persistent genetic variant LCT-13910 C/T (rs4988235), a proxy for long-term low and high intake of milk, and mortality. We used two Danish population-based studies with self-reported intake of milk and genotyping for LCT-13910 C/T. We obtained information on all-cause and cause-specific mortality (cardiovascular and cancer) from the national Danish registries. We used multivariable adjusted Cox regression to assess the association between milk intake and mortality in 74,241 individuals, and both logistic and Cox-regression to assess the association between genetic lactase persistence and mortality in 82,964 individuals using a Mendelian randomization design. We applied per T-allele, co-dominant and dominant models. During a mean follow-up of 7 years, 9759 individuals died, 2166 from cardiovascular disease, and 2822 from cancer. Observationally, there was no association between intake of skimmed milk and all-cause or cardiovascular mortality, and we did not find any associations between intake of semi-skimmed or whole milk with all-cause or cause-specific mortality. Intake of skimmed milk was associated with lower cancer mortality with a hazard ratio of 0.97 (95% CI 0.96–1.00) per doubling in milk intake. Per T-allele, milk intake increased with 0.58 (0.50–0.68) glasses/week. Genetically, we found no associations between the lactase persistent LCT-13910 C/T genotype and all-cause or cause-specific mortality; per T-allele OR (95% CI) for all-cause mortality was 1.02 (0.97–1.06). Our study did not provide strong evidence of observational or genetic associations between milk intake and all-cause or cause-specific mortality.

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References

  1. Itan Y, Powell A, Beaumont MA, Burger J, Thomas MG. The origins of lactase persistence in Europe. PLoS Comput Biol. 2009;5(8):e1000491. doi:10.1371/journal.pcbi.1000491.

    Article  PubMed  PubMed Central  Google Scholar 

  2. O’Sullivan TA, Hafekost K, Mitrou F, Lawrence D. Food sources of saturated fat and the association with mortality: a meta-analysis. Am. J Public Health. 2013;103(9):e31–42. doi:10.2105/AJPH.2013.301492.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Tognon G, Nilsson LM, Shungin D, et al. Nonfermented milk and other dairy products: associations with all-cause mortality. Am J Clin Nutr. 2017;105(6):1502–11. doi:10.3945/ajcn.116.140798.

    CAS  PubMed  Google Scholar 

  4. Guo J, Astrup A, Lovegrove JA, Gijsbers L, Givens DI, Soedamah-Muthu SS. Milk and dairy consumption and risk of cardiovascular diseases and all-cause mortality: dose–response meta-analysis of prospective cohort studies. Eur J Epidemiol. 2017;32(4):269–87. doi:10.1007/s10654-017-0243-1.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. Soedamah-Muthu SS, Ding EL, Al-Delaimy WK, et al. Milk and dairy consumption and incidence of cardiovascular diseases and all-cause mortality: dose–response meta-analysis of prospective cohort studies. Am J Clin Nutr. 2011;93(1):158–71. doi:10.3945/ajcn.2010.29866.

    CAS  Article  PubMed  Google Scholar 

  6. Mullie P, Pizot C, Autier P. Daily milk consumption and all-cause mortality, coronary heart disease and stroke: a systematic review and meta-analysis of observational cohort studies. BMC Public Health. 2016;16(1):1236. doi:10.1186/s12889-016-3889-9.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Lu W, Chen H, Niu Y, Wu H, Xia D, Wu Y. Dairy products intake and cancer mortality risk: a meta-analysis of 11 population-based cohort studies. Nutr J. 2016;15(1):91. doi:10.1186/s12937-016-0210-9.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Larsson SC, Crippa A, Orsini N, Wolk A, Michaëlsson K. Milk consumption and mortality from all causes, cardiovascular disease, and cancer: a systematic review and meta-analysis. Nutrients. 2015;7(9):7749–63. doi:10.3390/nu7095363.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. Lawlor DA, Harbord RM, Sterne JAC, Timpson N, Davey Smith G. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Stat Med. 2008;27(8):1133–63. doi:10.1002/sim.3034.

    Article  PubMed  Google Scholar 

  10. Enattah NS, Sahi T, Savilahti E, Terwilliger JD, Peltonen L, Järvelä I. Identification of a variant associated with adult-type hypolactasia. Nat Genet. 2002;30(2):233–7.

    CAS  Article  PubMed  Google Scholar 

  11. Bergholdt HK, Nordestgaard BG, Ellervik C. Milk intake is not associated with low risk of diabetes or overweight-obesity: a Mendelian randomization study in 97,811 Danish individuals. Am J Clin Nutr. 2015;102(2):487–96. doi:10.3945/ajcn.114.105049.

    CAS  Article  PubMed  Google Scholar 

  12. Bergholdt HKM, Nordestgaard BG, Varbo A, Ellervik C. Milk intake is not associated with ischaemic heart disease in observational or Mendelian randomization analyses in 98 529 Danish adults. Int J Epidemiol. 2015;44(2):587–603. doi:10.1093/ije/dyv109.

    Article  PubMed  Google Scholar 

  13. Smith CE, Coltell O, Sorli JV, et al. Associations of the MCM6-rs3754686 proxy for milk intake in Mediterranean and American populations with cardiovascular biomarkers, disease and mortality: Mendelian randomization. Sci Rep. 2016;6:33188. doi:10.1038/srep33188.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. Ellervik C, Tybjaerg-Hansen A, Nordestgaard BG. Total mortality by transferrin saturation levels: two general population studies and a metaanalysis. Clin Chem. 2011;57(3):459–66. doi:10.1373/clinchem.2010.156802.

    CAS  Article  PubMed  Google Scholar 

  15. Pedersen CB. The Danish civil registration system. Scand J Public Health. 2011;39(7 Suppl):22–5. doi:10.1177/1403494810387965.

    Article  PubMed  Google Scholar 

  16. Helweg-Larsen K. The Danish register of causes of death. Scand J Public Health. 2011;39(7 Suppl):26–9. doi:10.1177/1403494811399958.

    Article  PubMed  Google Scholar 

  17. Katan MB. Apolipoprotein E isoforms, serum cholesterol, and cancer. Lancet. 1986;1(8479):507–8.

    CAS  Article  PubMed  Google Scholar 

  18. VanderWeele TJ, Tchetgen Tchetgen EJ, Cornelis M, Kraft P. Methodological challenges in mendelian randomization. Epidemiology. 2014;25(3):427–35. doi:10.1097/EDE.0000000000000081.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Michaëlsson K, Wolk A, Langenskiöld S, et al. Milk intake and risk of mortality and fractures in women and men: cohort studies. BMJ. 2014;349:g6015.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Cui X, Wang L, Zuo P, et al. D-galactose-caused life shortening in Drosophila melanogaster and Musca domestica is associated with oxidative stress. Biogerontology. 2004;5(5):317–25. doi:10.1007/s10522-004-2570-3.

    CAS  Article  PubMed  Google Scholar 

  21. Hettinga K. Study used wrong assumption about galactose content of fermented dairy products. BMJ. 2014;349:g7000.

    Article  PubMed  Google Scholar 

  22. Alm L. Effect of fermentation on lactose, glucose, and galactose content in milk and suitability of fermented milk products for lactose intolerant individuals. J Dairy Sci. 1982;65(3):346–52. doi:10.3168/jds.S0022-0302(82)82198-X.

    CAS  Article  PubMed  Google Scholar 

  23. Ding M, Huang T, Bergholdt HK, et al. Dairy consumption, systolic blood pressure, and risk of hypertension: Mendelian randomization study. BMJ. 2017;356:j1000. doi:10.1136/bmj.j1000.

    Article  PubMed  Google Scholar 

  24. Yang Q, Lin SL, Au Yeung SL, et al. Genetically predicted milk consumption and bone health, ischemic heart disease and type 2 diabetes: a Mendelian randomization study. Eur J Clin Nutr. 2017;71(8):1008–12. doi:10.1038/ejcn.2017.8.

    CAS  Article  PubMed  Google Scholar 

  25. Aune D, Lau R, Chan DS, et al. Dairy products and colorectal cancer risk: a systematic review and meta-analysis of cohort studies. Ann Oncol. 2012;23(1):37–45. doi:10.1093/annonc/mdr269.

    CAS  Article  PubMed  Google Scholar 

  26. Dik VK, Murphy N, Siersema PD, et al. Prediagnostic intake of dairy products and dietary calcium and colorectal cancer survival–results from the EPIC cohort study. Cancer Epidemiol Biomarkers Prev. 2014;23(9):1813–23. doi:10.1158/1055-9965.EPI-14-0172.

    CAS  Article  PubMed  Google Scholar 

  27. Itan Y, Jones BL, Ingram CJ, Swallow DM, Thomas MG. A worldwide correlation of lactase persistence phenotype and genotypes. BMC Evol Biol. 2010;10:36. doi:10.1186/1471-2148-10-36.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Schatzkin A, Abnet CC, Cross AJ, et al. Mendelian randomization: how it can-and cannot-help confirm causal relations between nutrition and cancer. Cancer Prev Res (Phila). 2009;2(2):104–13. doi:10.1158/1940-6207.CAPR-08-0070.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We are grateful to all participants and staff in the Copenhagen General Population Study and the Copenhagen City Heart Study for their valuable contributions.

Funding

The Copenhagen General Population Study was funded by The Danish Council for Independent Research; Medical Sciences(FSS); Herlev and Gentofte Hospital, Copenhagen University Hospital; Copenhagen County Foundation; and Chief Physician Johan Boserup and Lise Boserup’s Fund, Denmark. The Copenhagen City Heart Study was funded by the Danish Heart Foundation. HKMB’s PhD project was partly funded by the Danish Dairy Research Foundation; the Research Unit at Naestved Hospital, Denmark; and the Regional Research Unit in Region Zealand, Denmark. None of the funding sources were involved in the design, conduct of study, collection, management, analysis, or interpretation of data, or in preparation of the manuscript, and were not involved in the decision to submit the manuscript.

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Contributions

Authors responsible for this article are Helle KM Bergholdt(HKMB), Børge G Nordestgaard(BGN), Anette Varbo(AV) and Christina Ellervik(CE). BGN and CE conceived and designed the research and acquired the data. Literature search was performed by HKMB. HKMB prepared the data, performed statistical analyses, and drafted the manuscript. All authors undertook critical revisions of the manuscript and contributed intellectually to the development of this paper, as well as performed final approval of the paper. All authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data in the analyses, and affirm that the manuscript is an honest, accurate, and transparent account of the study being reported and that no important aspects of the study have been omitted.

Corresponding author

Correspondence to Christina Ellervik.

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Conflicts of interest

All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author). Dr Bergholdt reports grant from the Danish Dairy Research Foundation during the conduct of the study. Dr Nordestgaard, Dr Varbo, and Dr Ellervik report no conflicts of interest.

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Bergholdt, H.K.M., Nordestgaard, B.G., Varbo, A. et al. Lactase persistence, milk intake, and mortality in the Danish general population: a Mendelian randomization study. Eur J Epidemiol 33, 171–181 (2018). https://doi.org/10.1007/s10654-017-0328-x

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  • DOI: https://doi.org/10.1007/s10654-017-0328-x

Keywords

  • Dairy
  • Milk
  • Mortality
  • Lactose
  • LCT-13910
  • Lactase persistence