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.
Highlights
With higher cardiovascular disease (CVD) and mortality risk in women but not in men (P-sex interaction:0.005 and 0.032, respectively), mainly in the Mediterranean Diet (MedDiet) group
The results of our meta-analysis suggest a greater association of the T-allele with milk intake in women, but this heterogeneity by sex needs to be confirmed in other populations in order to better assess its importance
This marker may be more appropriate as an instrumental variable of milk intake in Mediterranean and American populations than the maintenance complex component 6 (MCM6)-rs4988235, originating in Northern Europe[11], as there are previous studies that have found that the MCM6-rs4988235 does not predict milk intake in all populations[12,13,14,15]
Summary
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. Whereas evidence has accumulated regarding sex-specific differences in CVD incidence and risk factors[16,17,18], as well as some sex-specific effects of several SNPs for CVD19,20, the implications of sex differences in Mendelian randomization studies have received less attention Analysis of these sex-specific differences is needed as it may help us to strengthen causal inference, as previously reported[21]. Sex differences in dairy product consumption have been reported[22] and lactose intolerance, as subjectively experienced, varies by sex, being higher in women[23] Another important aspect to consider in Mendelian randomization studies for outcomes as complex as CVD or mortality, is the dietary context (e.g., dietary pattern) in which the food of interest is consumed[24]. This randomized, controlled trial allowed us to further analyze the influence of the dietary context on the SNP associations with CVD and mortality
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