Abstract
Triglyceride (TG)/HDL-C ratio (THR) is a surrogate predictor of hyperinsulinemia. To identify novel genetic loci for THR change over time (ΔTHR), we conducted genome-wide association study (GWAS) and genome-wide linkage scan (GWLS) among nondiabetic Europeans from the Long Life Family Study (n ¼ 1,384). Subjects with diabetes or on dyslipidemia medications were excluded. ΔTHR was derived using growth curve modeling and adjusted for age, sex, field centers, and principal components. GWAS used a linear mixed model accounting for familial relatedness. GWLS employed haplotypebased identity-by-descent estimation with 0.5 cM average spacing. Heritability of ΔTHR was moderate (46%). Our GWAS identified a significant locus at the LPL (P ¼ 1.58e-9) for ΔTHR; this locus has been reported before influencing baseline THR levels. Our GWLS found significant linkage with a logarithm of the odds exceeding 3 on 3q28 (logarithm of the odds ¼ 4.1). Using a subset of 25 linkage-enriched families, we assessed sequence elements under 3q28 and identified two novel variants (EIF4A2 [eukaryotic translation initiation factor 4A2]/ADIPOQ-rs114108468, p ¼ 5e-6, minor allele frequency ¼ 1.8%; TPRG1-rs16864075, p ¼ 3e-6, minor allele frequency ¼ 8%; accounted for ∼28% and ∼29% of the linkage, respectively). While the former variant was associated with EIF4A2 (p ¼ 7e-5)/ADIPOQ (P ¼ 3.49e-2) transcriptional levels, the latter variant was not associated with TPRG1 (P ¼ 0.23) transcriptional levels. Replication in the Framingham Heart Study Offspring Cohort observed modest effect of these loci on ΔTHR. Our approach discovered two novel gene variants EIF4A2/ADIPOQ-rs114108468 and TPRG1-rs16864075 on 3q28 for ΔTHR among subjects without diabetes. Our findings provided novel insights into the molecular regulation of insulin resistance.
Original language | English |
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Article number | 100702 |
Journal | Journal of lipid research |
Volume | 66 |
Issue number | 1 |
DOIs | |
State | Published - Jan 2025 |
Keywords
- aging
- genome-
- GWAS
- insulin resistance
- multiomics analyses
- wide linkage scan