Association of lactase persistence genotype with milk consumption, obesity and blood pressure: a Mendelian randomization study in the 1982 Pelotas (Brazil) Birth Cohort, with a systematic review and meta-analysis

Abstract

Background: Milk intake has been associated with lower blood pressure (BP) in observational studies, and randomized controlled trials suggested that milk-derived tripeptides have BP-lowering effects. Milk intake has also been associated with body mass index (BMI). Nevertheless, it is unclear whether increasing milk consumption would reduce BP in the general population. Methods: We investigated the association of milk intake with obesity and BP using genetically-defined lactase persistence (LP) based on the rs4988235 polymorphism in a Mendelian randomization design in the 1982 Pelotas (Southern Brazil) Birth Cohort. These results were combined with published reports identified through a systematic review using meta-analysis. Results: In the 1982 Pelotas Birth Cohort, milk intake was 42 [95% confidence interval (CI): 18; 67) ml/day higher in LP individuals. In conventional observational analysis, each 1-dl/day increase in milk intake was associated with −0.26 (95% CI: −0.33; −0.19) kg/m2 in BMI and −0.31 (95% CI: −0.46; −0.16) and -0.35 (95% CI: −0.46; −0.23) mmHg in systolic and diastolic BP, respectively. These results were not corroborated when analysing LP status, but confidence intervals were large. In random effects meta-analysis, LP individuals presented higher BMI [0.17 (95% CI: 0.07; 0.27) kg/m2] and higher odds of overweight-obesity [1.09 (95% CI: 1.02; 1.17)]. There were no reliable associations for BP. Conclusions: Our study supports that LP is positively associated with obesity, suggesting that the negative association of milk intake with obesity is likely due to limitations of conventional observational studies. Our findings also do not support that increased milk intake leads to lower BP.

Dairy Consumption and Body Mass Index Among Adults: Mendelian Randomization Analysis of 184802 Individuals from 25 Studies

“…Therefore, MR is analogous to an RCT and can be used to support the hypothesis that the association of dairy intake with BMI is causal. Recently, a genetic analysis from the 1982 Pelotas (Brazil) Birth Cohort (26) did not support a causal relationship between high dairy intake and increased BMI. However, this study was limited by small sample size (n = 2808) and low power to derive valid conclusions.…”

Complex Interactions of Obesity, Dairy Food Intake and Genetics of Lactase

“…Among the 3 studies using Mendelian randomization Hartwig et al found an important difference in outcome between the use of Mendelian randomization and conventional analysis. The significant decrease in weight with 1 dl/day intake of milk, was abrogated when the former method was applied [105]. In the large Danish study by Bergholdt et al the hypothesized negative association of dairy intake with overweight-obesity was not found [104].…”

“…One caveat is there should be no horizontal pleiotropy, where the genetic trait affects the outcome independent of exposure [97]. Table 2 outlines 10 studies which have examined the association between lactase persistence, features of obesity and dairy intake [98][99][100][101][102][103][104][105][106][107]. Three studies only evaluated relationship between lactase persistence status and obesity [98,102,106].…”

“…Three of the 10 studies were restricted to children or young adults [102,103,106]. Three studies carried out Mendelian randomization methods [104,105,107]. All studies evaluated the north European polymorphism C/T-13910 as an indicator of lactase persistence (TT, CT dominant trait) or lactase non persistence (CC recessive trait).…”

Causal inference in obesity research

“…Eight Mendelian randomization studies examining the effects of environmental exposures on BMI have been published. These include three studies on milk consumption and its effect on BMI, with two small studies reporting weak evidence of a causal effect and one large study ( n = 97 811) reporting no clear effect . Two large studies on the effects of smoking on anthropometric indices of body corpulence reported that the instrument for smoking was causally related to narrower hip circumference and lower BMI .…”