A genome-wide linkage analysis for circulating vascular adhesion protein -1 levels:MACROD2 as a regulator of adipogenesis

• Main Authors: Jiun-Yi Nong, 農君怡
• Other Authors: Fang-Jen Lee
• Format: Others
• Language: en_US
• Published: 2017
• Online Access: http://ndltd.ncl.edu.tw/handle/swh726

碩士 === 國立臺灣大學 === 分子醫學研究所 === 105 === 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.