Abstract
BackgroundHigh 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.MethodsWe 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).ResultsIn 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) (Pmeta-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 < 1.37 × 10−6) and lower LDL-C (P = 3.60 × 10−6), TC (P = 1.90 × 10−6) and HDL-C (P = 3.00 × 10−5).ConclusionsOur large-scale MR study provides genetic evidence for the association of milk consumption with higher BMI but lower serum cholesterol levels. These data suggest no need to limit milk intakes with respect to cardiovascular disease risk, with the suggested benefits requiring confirmation in further studies.
Highlights
High milk intake has been associated with cardio-metabolic risk
The odds of consuming milk was higher for the ‘T’ allele carriers of the LCT variant (SNP rs4988235) compared to the CC homozygotes (OR: 2.14, 95% CI: 1.57–2.93, P = 1.68 × 10−6 for the 1958 British Birth cohort (1958BC); OR 1.21, 95% CI: 1.09–1.34, P = 3.0 × 10−4 for the UK Biobank)
Using a two-sample Mendelian Randomization (MR) analysis, we confirmed the causality between genetically instrumented high milk intake and higher body mass index (BMI) and lower low-density lipoprotein cholesterol (LDL-C), total cholesterol and high-density lipoprotein cholesterol (HDL-C)
Summary
High milk intake has been associated with cardio-metabolic risk. Diet is a major determinant of cardio-metabolic diseases [4] and several studies have shown associations between dairy and milk consumption and cardio-metabolic risk factors [5,6,7,8,9,10]. High fat dairy products can lead to adverse effects on cardiovascular risk by increasing the intake of saturated fat and cholesterol which have been shown to increase blood cholesterol and subsequent risk of cardiovascular diseases (CVDs) [11, 12]. Milk is a major source of calcium and a risk factor for arterial calcification [13] Despite these proposed adverse effects, a reduced risk of CVDs was reported for consumption of milk and low-fat dairy products in large scale meta-analysis of data from nine studies (N = 57,256) [8]. The findings from randomised controlled trials (RCTs) have been inconsistent [14], failing to provide causal evidence either for a beneficial or adverse causal association
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