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
Division of Statistical Genomics, Washington University School of Medicine, St. Louis, MO, USA.
Division of Statistical Genomics, Washington University School of Medicine, St. Louis, MO, USA.
J Lipid Res. 2025 Jan;66(1):100702. doi: 10.1016/j.jlr.2024.100702. Epub 2024 Nov 16.
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.
甘油三酯（TG）/高密度脂蛋白胆固醇（HDL-C）比值（THR）是高胰岛素血症的替代预测指标。为了确定随时间变化的THR（ΔTHR）的新遗传位点，我们在长寿家庭研究中的非糖尿病欧洲人（n = 1384）中进行了全基因组关联研究（GWAS）和全基因组连锁扫描（GWLS）。排除患有糖尿病或正在服用血脂异常药物的受试者。使用生长曲线模型得出ΔTHR，并对年龄、性别、研究中心和主成分进行了调整。GWAS使用了考虑家族相关性的线性混合模型。GWLS采用基于单倍型的同源性估计，平均间距为0.5 cM。ΔTHR的遗传度为中等（46%）。我们的GWAS在脂蛋白脂肪酶（LPL）基因座发现了一个与ΔTHR相关的显著位点（P = 1.58e-9）；该位点之前已有报道会影响基线THR水平。我们的GWLS发现3q28上的优势对数超过3的显著连锁（优势对数 = 4.1）。使用25个富含连锁的家系子集，我们评估了3q28区域的序列元件，确定了两个新变异（真核翻译起始因子4A2 [EIF4A2]/脂联素基因-rs114108468，p = 5e-6，次要等位基因频率 = 1.8%；TPRG1基因-rs16864075，p = 3e-6，次要等位基因频率 = 8%；分别占连锁的约28%和约29%）。虽然前一个变异与EIF4A2（p = 7e-5）/脂联素（P = 3.49e-2）的转录水平相关，但后一个变异与TPRG1（P = 0.23）的转录水平无关。在弗雷明汉心脏研究后代队列中的重复研究观察到这些位点对ΔTHR有适度影响。我们的方法在无糖尿病受试者中发现了位于3q28上的两个新基因变异EIF4A2/脂联素基因-rs114108468和TPRG1基因-rs16864075与ΔTHR相关。我们的发现为胰岛素抵抗的分子调控提供了新的见解。
