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

Background High milk intake has been associated with cardio-metabolic risk. We conducted a Mendelian Randomization (MR) study to obtain evidence for the causal relationship between milk consumption and cardio-metabolic traits using the lactase persistence ( LCT -13910 C > T, rs4988235) variant as an instrumental variable. Methods We tested the association of LCT genotype with milk consumption (for validation) and with cardio-metabolic traits (for a possible causal association) in a meta-analysis of the data from three large-scale population-based studies (1958 British Birth Cohort, Health and Retirement study, and UK Biobank) with up to 417,236 participants and using summary statistics from consortia meta-analyses on intermediate traits ( N = 123,665–697,307) and extended to cover disease endpoints ( N = 86,995–149,821). Results In the UK Biobank, carriers of ‘T’ allele of LCT variant were more likely to consume milk ( P = 7.02 × 10 −14 ). In meta-analysis including UK Biobank, the 1958BC, the HRS, and consortia-based studies, under an additive model, ‘T’ allele was associated with higher body mass index (BMI) ( P meta-analysis = 4.68 × 10 −12 ) and lower total cholesterol (TC) ( P = 2.40 × 10 −36 ), low-density lipoprotein cholesterol (LDL-C) ( P = 2.08 × 10 −26 ) and high-density lipoprotein cholesterol (HDL-C) ( P = 9.40 × 10 −13 ). In consortia meta-analyses, ‘T’ allele was associated with a lower risk of coronary artery disease (OR:0.86, 95% CI:0.75–0.99) but not with type 2 diabetes (OR:1.06, 95% CI:0.97–1.16). Furthermore, the two-sample MR analysis showed a causal association between genetically instrumented milk intake and higher BMI ( P = 3.60 × 10 −5 ) and body fat (total body fat, leg fat, arm fat and trunk fat; P