Novel Loci for Triglyceride / High-density Lipoprotein Cholesterol Ratio Longitudinal Change among Subjects without Type 2 Diabetes.

Aims/hypothesis: Triglyceride (TG) /High density lipoprotein cholesterol (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 non-diabetic Europeans from the Long Life Family Study (LLFS, n=1384).

Methods: 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 (PCs). GWAS used a linear mixed model accounting for familial relatedness. GWLS employed haplotype-based IBD estimation with 0.5 cM average spacing.

Results: Heritability of ΔTHR was moderate (46%). Our GWAS identified a significant locus at the LPL (p=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 (LODs) exceeding 3 on 3q28 (LODs=4.1). Using a subset of 25 linkage enriched families, we assessed sequence elements under 3q28 and identified two novel variants (EIF4A2/ADIPOQ-rs114108468, p=5e-6, MAF=1.8%; TPRG1-rs16864075, p=3e-6, MAF=8%; accounted for ∼28% and ∼29% of the linkage, respectively). While the former variant was associated with EIF4A2 (p=7e-5) / ADIPOQ (p=3.49e-2) transcriptional levels, the latter variant was not associated with TPRG1 (p=0.23) transcriptional levels. Replication in the Framingham Heart Study Offspring Cohort (FOS) observed modest effect of these loci on ΔTHR.

Conclusions: 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.