Novel loci for triglyceride/HDL-C ratio longitudinal change among subjects without T2D

• Published in: Journal of lipid research Vol. 66; no. 1; p. 100702
• Main Authors: Wang, Lihua, Wang, Siyu, Anema, Jason A., Moghaddam, Vaha A., Lu, Yanli, Lin, Shiow, Daw, E. Warwick, Kuipers, Allison L., Miljkovic, Iva, Brent, Michael, Patti, Gary J., Thygarajan, Bharat, Zmuda, Joseph M., Province, Michael A., An, Ping
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2025; American Society for Biochemistry and Molecular Biology; Elsevier
• Subjects: Adult; Aged; aging; Cholesterol, HDL - blood; Cholesterol, HDL - genetics; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - genetics; Female; Genetic Loci; Genome-Wide Association Study; genome-wide linkage scan; GWAS; Humans; insulin resistance; Longitudinal Studies; Male; Middle Aged; multiomics analyses; Polymorphism, Single Nucleotide; Triglycerides - blood; Triglycerides - genetics; genome-wide linkage scan; LOD; WGS; GWAS; multiomics analyses; IR; FOS; LLFS; MGI; QC; MAF; PC; TG; GWLS; SOLAR; ALFA; HLOD; LD; aging; insulin resistance; THR
• ISSN: 0022-2275; 1539-7262; 1539-7262
• DOI: 10.1016/j.jlr.2024.100702

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 = 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 haplotype-based 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 = 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 = 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 = 5e-6, minor allele frequency = 1.8%; TPRG1-rs16864075, p = 3e-6, minor allele frequency = 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 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.