Genome‐wide scan for circulating vascular adhesion protein‐1 levels: MACROD2 as a potential transcriptional regulator of adipogenesis

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 9 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 (MACROD2) gene in females (P = 5.38 9 10 -6

Congenital heart disease risk loci identified by genome-wide association study in European patients

“…In the TGA subgroup, SNPs on chromosomes 20 and 8 were identified. The lead SNP (rs150246290) and three variants on chromosome 20, all with genome-wide significance, mapped to the MACROD2 gene ( Figure 2A) implicated in chromosomal instability (26) and transcriptional regulation (27). Two SNPs (rs149890280, rs150246290) are suggested to be possible causal variants (Supplemental Table 1).…”

The Controversial Roles of ADP-Ribosyl Hydrolases MACROD1, MACROD2 and TARG1 in Carcinogenesis

“…In another genome-wide association study, MACROD2 was identified as a factor influencing vascular-adhesion protein-1 (VAP-1) levels, which the authors confirmed by knockdown of MACROD2. This leads to lower VAP-1 expression in adipocytes, presumably through the transcriptional regulation of VAP-1 [82]. MACROD2 was also reported to leave the nucleus upon DNA damage, dependent on phosphorylation by ATM [75], whereas TARG1 localises from nucleoli to nuclear sites of damage [14], which both have an unclear functional relevance.…”

Genome-wide association study in European patients with congenital heart disease identifies risk loci for transposition of the great arteries and anomalies of the thoracic arteries and veins and expression of discovered candidate genes in the developing heart

“…The lead SNP (rs150246290) and three variants on chromosome 20, all with genome-wide significance, mapped to the MACROD2 gene ( Figure 2A) implicated in chromosomal instability 25 and transcriptional regulation. 26 Two SNPs (rs149890280, rs150246290) are suggested to be possible causal variants ( Table I in Figure 2B). Given the high levels of linkage disequilibrium between these SNPs, they are indicative of the same association signal in both loci.…”

“…In the TGA subgroup, four SNPs with genome-wide significance mapped to MACROD2 which has been linked to adipogenesis and hypertension. 26,33 Microdeletions in this gene have been implicated as a cause of chromosomal instability in cancers 34 and de novo deletion of exon 5 causes Kabuki syndrome. 35 Chromosomal imbalance is also frequently seen in CHD patients with different morphologies [36][37][38][39] including TGA 40 but so far the MACROD2 locus was not associated with CHD.…”