External factors shape genetic predisposition to lipids, Alzheimer’s and heart disease in the MLXIPL gene

A new research paper entitled “Exogenous exposures shape genetic predisposition to lipids, Alzheimer’s and coronary heart disease at the MLXIPL gene locus” has been published in Aging.

In this new study, researchers from Duke University, University of Pittsburgh and Washington University School of Medicine examined associations of single nucleotide polymorphisms (SNPs) of the MLXIPL lipid gene with Alzheimer’s (AD) and coronary heart disease (CHD) and potentially causal mediating effects. of their risk factors, high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) in two samples of European ancestry from the United States (US) (22,712 subjects; 587/2,608 AD/CHD cases) and the United Kingdom Biobank (UKB) (232,341 subjects; 809/15,269 AD/CHD cases).

The researchers postulate, “Our results suggest that these associations may be regulated by several biological mechanisms and shaped by exogenous exposures.”

Two association patterns (represented by rs17145750 and rs6967028) were identified. The minor alleles of rs17145750 and rs6967028 demonstrated primary (secondary) association with high TG levels (lower HDL-C) and high HDL-C (lower TG), respectively. The primary association explained ~50% of the secondary, suggesting partially independent mechanisms of TG and HDL-C regulation. The magnitude of the association of rs17145750 with HDL-C was significantly greater in the US versus UKB sample and likely related to differences in exogenous exposures in the two countries. rs17145750 demonstrated a significant detrimental indirect effect via TG on AD risk in UKB only (βIE = 0.015, pIE = 1.9 × 10⁻³), suggesting protective effects of high TG levels against AD, likely shaped by exogenous exposures.

Furthermore, rs17145750 demonstrated significant protective indirect effects through TG and HDL-C on associations with CHD in both samples. In contrast, rs6967028 demonstrated an adverse mediation effect through HDL-C on CHD risk in the US sample only (βIE = 0.019, pIE = 8.6 × 10⁻⁴). This compensation suggests different roles of triglyceride-mediated mechanisms in the pathogenesis of AD and CHD.

The researchers conclude: “Finally, the results of this study suggest that the genetic associations of SNPs from the MLXIPL gene locus with lipids, AD, and CHD are shaped by exogenous exposures. Further study of related biological mechanisms may help to elucidate the related, modifiable risk factors”.

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