Causal association between milk intake and cardiometabolic risk factors

Evidence for a causal association between milk intake and cardiometabolic disease outcomes using a two-sample Mendelian Randomization analysis in up to 1,904,220 individuals

Literature - Vimaleswaran KS, Zhou A, Cavadino A, et al., - Int J Obes 2021; doi: 10.1038/s41366-021-00841-2

Introduction and methods

A causal association was found between greater dairy intake and higher body mass index, but not for CVD [1-3]. It is not clear whether consumption of milk and dairy products has a beneficial or adverse effect on risk of CVD [4].

In Mendelian randomization studies that examined the association between milk intake and diseases, the SNP rs4988235 upstream of the gene for the lactase enzyme has been used as a marker of milk intake [5-7]. The lactase enzyme plays a role in the digestion of milk sugar lactose and is encoded by the lactase (LCT) gene. The SNP rs4988235 affects the transcription of LCT and differences in this SNP result in phenotypes of lactase. The T allele was associated with lactase persistence and increase LCT gene promoter activity.

This Mendelian Randomization study investigated the association between milk consumption and CVD, T2DM and cardio-metabolic risk factors, including measures of adiposity, blood pressure, and markers of chronic inflammation, lipid and glucose metabolism.

The study included data of 417, 236 individuals from 3 large population-based studies (British Birth cohort, Health Retirement Study and UK Biobank). Information on milk intake was available from the British Birth cohort and the UK Biobank. SNP rs4988235 was genotyped in the 3 cohorts. Summary statistics data from several large consortia-based studies (GIANT, Global Lipids, MAGIC, ICBP, DIAGRAM, CARDIOGRAM, EPIC-InterAct (n=1,486,984) were also used for the meta-analysis.

Main results

  • Odds of consuming milk was higher for the T allele carriers of the LCT variant compared to the CC homozygotes (OR 2.14, 95%CI:1.57-2.93, P=1.68x10-6 for the British Birth cohort and OR was 1.21, 95%CI:1.09-1.34, P=3.0x10-4 for the UK Biobank).
  • Meta-analysis of data from the British Birth cohort and UK Biobank showed a phenotypic association between high milk intake and lower HDL-c (P=2.70x10-6), and higher triglycerides (P=0.001), and CRP (P=2.60x10-30).
  • In the meta-analysis, the T allele (indexing greater milk intake) was associated with higher BMI (P=4.68x10-12), lower LDL-c (P=2.08x10-26), HDL-c (P=9.40x10-13), and total cholesterol (P=2.38x10-36).
  • Using estimates from the meta-analysis and estimates of the LCT variant-milk intake association from the EPIC-InterAct study, the MR analysis confirmed the association of genetically instrumented high milk intake with higher BMI (P=3.60x10-5), lower LDL-c (P=3.60x10-6), total cholesterol (P=1.90x10-6), and HDL-c (P=3.00x10-5).


A large-scale meta-analysis showed that the T allele of the LCT SNP rs49883235 indexing for greater milk intake was associated with CV-related risk factors, such as BMI, LDL-c and total cholesterol. Two-sample Mendelian randomization analysis confirmed the association between genetically instrumented greater milk intake and higher BMI, lower LDL-c, total cholesterol and HDL-c.

‘Large intervention trials are needed to establish the causal link between high milk consumption and cardio-metabolic phenotypes before changes in dairy consumption could be recommended for the prevention of cardiometabolic traits’, according to the authors.


1. Mendelian Randomization of Dairy Consumption Working G. Dairy Consumption and Body Mass Index Among Adults: Mendelian Randomization Analysis of 184802 Individuals from 25 Studies. Clin Chem. 2018;64:183–91.

2. Mendelian Randomization of Dairy Consumption Working G, consortium C. Dairy Intake and Body Composition and Cardiometabolic Traits among Adults: Mendelian Randomization Analysis of 182041 Individuals from 18 Studies. Clin Chem. 2019;65:751–60.

3.. Ding M, Huang T, Bergholdt HK, Nordestgaard BG, Ellervik C, Qi L, et al. Dairy consumption, systolic blood pressure, and risk of hypertension: Mendelian randomization study. BMJ. 2017;356:j1000

4. Huth PJ, Park KM. Influence of dairy product and milk fat consumption on cardiovascular disease risk: a review of the evidence. Adv Nutr. 2012;3:266–85.

5. 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;102:487–96.

6.. Almon R, Nilsson TK, Sjostrom M, Engfeldt P. Lactase persistence and milk consumption are associated with body height in Swedish preadolescents and adolescents. Food Nutr Res. 2011;55:10.

7. Bergholdt HK, 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;44:587–603

Find this article online at Int J Obes

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