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

IF 5 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Lipid Research Pub Date : 2024-11-16 DOI:10.1016/j.jlr.2024.100702

Lihua Wang, Siyu Wang, Jason A Anema, Vaha A Moghaddam, Yanli Lu, Shiow Lin, E Warwick Daw, Allison L Kuipers, Iva Miljkovic, Michael Brent, Gary J Patti, Bharat Thygarajan, Joseph M Zmuda, Michael A Province, Ping An

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引用次数: 0

Abstract

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.

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无 2 型糖尿病受试者甘油三酯/高密度脂蛋白胆固醇比值纵向变化的新基因位点。

目的/假设：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THR随时间变化的新遗传位点（ΔTHR），我们在长寿家庭研究（LLFS，n=1384）的非糖尿病欧洲人中进行了全基因组关联研究（GWAS）和全基因组关联扫描（GWLS）：方法：排除患有糖尿病或服用血脂异常药物的受试者。通过生长曲线建模得出ΔTHR，并根据年龄、性别、现场中心和主成分（PC）进行调整。GWAS 采用线性混合模型，考虑了家族相关性。GWLS 采用基于单倍型的 IBD 估计，平均间距为 0.5 cM：结果：ΔTHR的遗传率为中等（46%）。我们的 GWAS 在 LPL（p=1.58e-9）上发现了一个影响 ΔTHR 的重要位点；该位点曾被报道影响基线 THR 水平。我们的 GWLS 在 3q28 上发现了几率对数（LOD）超过 3 的重要连锁（LOD=4.1）。我们使用 25 个关联富集家系的子集，评估了 3q28 下的序列元素，发现了两个新变异（EIF4A2/ADIPOQ-rs114108468，p=5e-6，MAF=1.8%；TPRG1-rs16864075，p=3e-6，MAF=8%；分别占关联的 28% 和 29%）。前一个变异与 EIF4A2（p=7e-5）/ADIPOQ（p=3.49e-2）的转录水平有关，而后一个变异与 TPRG1（p=0.23）的转录水平无关。在弗雷明汉心脏研究后代队列（FOS）中复制观察到这些位点对ΔTHR的影响不大：我们的方法发现了3q28上的两个新基因变异EIF4A2/ADIPOQ-rs114108468和TPRG1-rs16864075，这两个基因变异在无糖尿病的受试者中对ΔTHR有影响。我们的研究结果为胰岛素抵抗的分子调控提供了新的见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Lipid Research 生物-生化与分子生物学

CiteScore

11.10

自引率

4.60%

发文量

146

审稿时长

41 days

期刊介绍： The Journal of Lipid Research (JLR) publishes original articles and reviews in the broadly defined area of biological lipids. We encourage the submission of manuscripts relating to lipids, including those addressing problems in biochemistry, molecular biology, structural biology, cell biology, genetics, molecular medicine, clinical medicine and metabolism. Major criteria for acceptance of articles are new insights into mechanisms of lipid function and metabolism and/or genes regulating lipid metabolism along with sound primary experimental data. Interpretation of the data is the authors’ responsibility, and speculation should be labeled as such. Manuscripts that provide new ways of purifying, identifying and quantifying lipids are invited for the Methods section of the Journal. JLR encourages contributions from investigators in all countries, but articles must be submitted in clear and concise English.