Genome‐wide scan for circulating vascular adhesion protein‐1 levels: MACROD 2 as a potential transcriptional regulator of adipogenesis

• Published in: Journal of diabetes investigation Vol. 9; no. 5; pp. 1067 - 1074
• Main Authors: Chang, Yi‐Cheng, Hee, Siow‐Wey, Lee, Wei‐Jei, Li, Hung‐Yuan, Chang, Tien‐Jyun, Lin, Ming‐Wei, Hung, Yi‐Jen, Lee, I‐Te, Hung, Kuan‐Yi, Assimes, Themistocles, Knowles, Joshua W, Nong, Jiun‐Yi, Lee, Po‐Chu, Chiu, Yen‐Feng, Chuang, Lee‐Ming
• Format: Journal Article
• Language: English
• Published: Richmond John Wiley & Sons, Inc 01.09.2018
• Subjects: Adipocytes; Adipogenesis; Adipose tissue; Chromosome 20; Diabetes mellitus; Fatty liver; Gene loci; Gene mapping; Gene regulation; Heritability; Hypertension; Insulin; Liver diseases; Quantitative trait loci; Steatosis; Therapeutic applications; Transcription; United States > US; Taiwan; California
• ISSN: 2040-1116; 2040-1124
• DOI: 10.1111/jdi.12805

Abstract Aims/Introduction Vascular adhesion protein‐1 ( VAP ‐1) is a membrane‐bound amine oxidase highly expressed in mature adipocytes and released into the circulation. VAP ‐1 has been strongly implicated in several pathological processes, including diabetes, inflammation, hypertension, hepatic steatosis and renal diseases, and is an important disease marker and therapeutic target. Here, we aimed to identify the genetic loci for circulating VAP ‐1 levels. Materials and Methods We carried out a genomic‐wide linkage scan for the quantitative trait locus of circulating VAP ‐1 levels in 1,100 Han Chinese individuals from 398 families in the Stanford Asian Pacific Program for Hypertension and Insulin Resistance study. Regional association fine mapping was carried out using additional single‐nucleotide polymorphisms. Results The estimated heritability of circulating VAP ‐1 levels is high ( h 2 = 69%). The most significant quantitative trait locus for circulating VAP ‐1 was located at 38 cM on chromosome 20, with a maximum empirical logarithm of odds score of 4.11 ( P = 6.86 × 10 −6 ) in females. Regional single‐nucleotide polymorphism fine mapping within a 1‐unit support region showed the strongest association signals in the MACRO domain containing 2 ( MACROD 2 ) gene in females ( P = 5.38 × 10 −6 ). Knockdown of MACROD 2 significantly suppressed VAP ‐1 expression in human adipocytes, as well as the expression of key adipogenic genes. Furthermore, MACROD 2 expression was found to be positively associated with VAP ‐1 in human visceral adipose tissue. Conclusion MACROD 2 is a potential genetic determinant of serum VAP ‐1 levels, probably through transcriptional regulation of adipogenesis.