Associations of the MCM6-rs3754686 proxy for milk intake in Mediterranean and American populations with cardiovascular biomarkers, disease and mortality: Mendelian randomization

Abstract

Controversy persists on the association between dairy products, especially milk, and cardiovascular diseases (CVD). Genetic proxies may improve dairy intake estimations, and clarify diet-disease relationships through Mendelian randomization. We meta-analytically (n ≤ 20,089) evaluated associations between a lactase persistence (LP) SNP, the minichromosome maintenance complex component 6 (MCM6)-rs3754686C>T (nonpersistence>persistence), dairy intake, and CVD biomarkers in American (Hispanics, African-American and Whites) and Mediterranean populations. Moreover, we analyzed longitudinal associations with milk, CVD and mortality in PREDIMED), a randomized Mediterranean diet (MedDiet) intervention trial (n = 7185). The MCM6-rs3754686/MCM6-rs309180 (as proxy), LP-allele (T) was strongly associated with higher milk intake, but inconsistently associated with glucose and lipids, and not associated with CVD or total mortality in the whole population. Heterogeneity analyses suggested some sex-specific associations. The T-allele was associated with higher CVD and mortality risk in women but not in men (P-sex interaction:0.005 and 0.032, respectively), mainly in the MedDiet group. However, milk intake was not associated with CVD biomarkers, CVD or mortality either generally or in sub-groups. Although MCM6-rs3754686 is a good milk intake proxy in these populations, attributing its associations with CVD and mortality in Mediterranean women to milk is unwarranted, as other factors limiting the assumption of causality in Mendelian randomization may exist.

Intake of Milk or Fermented Milk Combined With Fruit and Vegetable Consumption in Relation to Hip Fracture Rates: A Cohort Study of Swedish Women

“…In addition, excess of galactose reacts non‐enzymatically with amino groups in proteins and peptides forming advanced glycation end‐products (AGEs) . Genetic lactase persistence as a proxy for higher milk intake in a Mendelian randomization study has recently been shown to be related to higher mortality and cardiovascular disease rates in women but not in men, although pleiotropy of the gene variant cannot be excluded . Nonetheless, we have also found similar sex differences in mortality rates in relation to milk intake …”

Milk Intake at Midlife and Cognitive Decline over 20 Years. The Atherosclerosis Risk in Communities (ARIC) Study

“…Only 9% of Whites where classified as LNP (as compared to previously reported 20%), and the SNP for LP/LNP among Blacks available in our study showed almost no variation. Considering that the estimated prevalence of LNP among Blacks in the US has been estimated at 80%, we concluded that the imputed SNP available in ARIC most likely did not characterize lactase persistence among Blacks [ 67 , 68 ].…”

Protective effect of homovanillyl alcohol on cardiovascular disease and total mortality: virgin olive oil, wine, and catechol-methylathion

“…In agreement with others (37), in this study we did not observe any association between COMT genotypes and total mortality. Taking into account the absence of a strong association between the COMT polymorphism and HVAL concentrations, as well as the high pleiotropy of the COMT enzyme, this polymorphism cannot be used as a proxy for Mendelian randomization (38). Therefore, the absence of associations between the COMT genotypes and CVD or total mortality cannot be interpreted as not causal.…”