Mediation of the APOE associations with Alzheimer ’s and coronary heart diseases through body mass index and lipids

AbstractTheAPOEε2/ε3/ε4 polymorphism is associated with multiple non-Mendelian traits, including high- (HDL-C) and low- (LDL-C) density lipoprotein cholesterol, triglycerides, body mass index (BMI), coronary heart disease (CHD), and Alzheimer’s disease (AD). Lipids and BMI are risk factors for AD and CHD. Cau sal connections between the ε2 and ε4 alleles and these traits remain, however, poorly understood. We leverage comprehensive analyses of longitudinal data from four studies to examine potentially causal heterogeneous connections between these alleles, lipids, BMI, and diseases. We emphasize mutual mediation roles of lipids and BMI in their associations with the ε2 and ε4 alleles and their mediation roles in the associations of these alleles with AD and CHD. We confirmed previously reported significant univariate associations of these alleles with each trait, except CHD. We found, however, that most of the univariate- and mediation-analysis associations were affected by antagonistic heterogeneity/mediation. The mutual mediation analysis identified the associations of theAPOE alleles with LDL-C as the least heterogeneous. The ε2 and ε4 alleles were associated with CHD through lipids, led by beneficial (βIE =  − 0.071,pIE = 2.28 × 10−10) and adverse (βIE = 0.019,pIE = 7.37 × 10−6) associations, respectively, through LDL-C. Both these alleles were adversely associated with CHD through triglycerides. For AD, only BMI partially ...
Source: AGE - Category: Geriatrics Source Type: research