血清VAP-1全基因組之連鎖分析: MACROD2 調節脂肪分化的角色

Abstract

背景:血管附著蛋白-1(VAP-1) 是一種在成熟脂肪細胞中強烈表現的胺氧化酶，它是可溶性蛋白質並可分泌到細胞外，而血清中VAP-1之濃度與多種疾病有相關。本研究目的是找尋調控VAP-1血中濃度之基因。 材料方法:本研究針對史丹佛大學亞太地區高血壓和胰島素阻抗性計畫(SAPPHIRe)收集的398個家庭的1,100名受試者，研究血清中VAP-1數值的數量性狀之全基因組連鎖分析。另外使用單核苷酸多態性(SNPs)進行局部相關性細定位。 結果:估算之血清VAP-1數值的遺傳度很高(h2=69%)，血清VAP-1的數量性狀基因最顯著的位於第20號染色體38cM的位點上，LOD值為2.29(P=5.81×10-4)，女性更為顯著(LOD: 4.11, P=6.86×10-6)。在LOD值最顯著的區域正負1之區間使用SNP進行局部相關細定位，結果顯示MACROD2(MACRO domain containing 2)基因具有強烈的關聯性，尤其是在女性(P=5.38×10-6)。將MACROD2基因之表現抑制會顯著抑制人類初級脂肪細胞中VAP-1的表現量以及其分泌到培養基中之蛋白量。剔除MACROD2也顯著抑制脂肪細胞的分化。MACROD2表現與人類內臟脂肪組織中的VAP-1表現量呈正相關。此外，VAP-1表現量也與身體質量指數，胰島素阻抗性與空腹胰島素數值的體內平衡模型呈正相關，並與高密度脂蛋白膽固醇數值呈負相關。 結論:本研究顯示MACROD2是血清VAP-1濃度的潛在的遺傳因子決定因素，機轉可能是通過調節脂肪細胞的分化而影響VAP-1之表現量。

Background, Vascular adhesion protein-1 (VAP-1) is an amine oxidase that is strongly expressed in mature adipocytes and excreted as a soluble protein. Serum VAP-1 levels are associated with various diseases. The aim of this study is to identify the genetic factor that modulates expression of VAP-1. Methods, We conducted a genome-wide linkage scan on 1,100 Han Chinese subjects from 398 families recruited in the Stanford Asian-Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) to map the quantitative trait loci (QTL) of circulating VAP-1 levels. We used additional single nucleotide polymorphisms (SNPs) association study for fine mapping. Results, The estimated heritability of circulating VAP-1 levels is high (h2=69%). The most significant QTL for circulating VAP-1 was located at 38 cM on chromosome 20, with a maximum empirical logarithm of odds (LOD) score of 2.29 (P=5.81×10-4), especially in females (LOD: 4.11, P=6.86×10-6). Regional SNP fine mapping within 1-unit support interval showed a strongest association signal in the MACROD2 (MACRO domain containing 2) gene, especially in females (P=5.38×10-6). The knockdown of MACROD2 significantly suppresses the expression of VAP-1 in primary human adipocytes and its secretion into the culture medium. Knockdown of MACROD2 also significantly suppresses the expression of key adipogenic genes. MACROD2 expression is positively associated with VAP-1 expression in human visceral adipose tissue. In addition, the expression level of VAP-1 is also positively associated with body mass index, homeostasis model assessment of insulin resistance (HOMA-IR) and fasting insulin levels and is negatively associated with high-density lipoprotein cholesterol (HDL-C) levels. Conclusion, Our study suggests MACROD2 is a potential genetic determinant of serumVAP-1 levels, probably through regulation of adipogenesis.