CDH13 gene coding t-cadherin influences variations in plasma adiponectin levels in the Japanese population

Abstract

Adiponectin is most abundantly expressed in adipose tissue and well known to play an important role in metabolic regulation. Several studies have attempted to identify the genetic determinants of metabolic syndrome (MetS), though no study has revealed a cis- or trans-single nucleotide polymorphism (SNP) that affects plasma adiponectin levels, except the adiponectin structure gene and genes encoding adiponectin-regulatory proteins. We performed a genome-wide association study in regards to plasma adiponectin concentrations in 3,310 Japanese subjects. We identified the strongest statistically associated SNP (rs4783244) with adiponectin levels (P = 3.8 × 10(-19)) in the first intron of CDH13 (T-cadherin) gene in a 30-kb haplotype block covering the promoter region to first intron. In addition, rs12051272 SNP genotypes in linkage disequilibrium with rs4783244 were found to be more significantly associated with adiponectin levels (P = 9.5×10(-20)) and specifically with the levels of high-molecular weight (HMW) adiponectin, a subtype form associated with parameters related to glucose metabolism. Our results did show more significant association with adiponectin levels than rs12444338 (in CDH13) SNP genotypes reported recently. We suggest that the phenotype-affecting haplotype tagged by rs12051272 SNP would affect the plasma adiponectin levels and that we have to take the CDH13 genotype into account before considering the functional relevance of the adiponectin level.

<i>CDH13</i> Polymorphisms are Associated with Adiponectin Levels and Metabolic Syndrome Traits Independently of Visceral Fat Mass

“…Tested alleles were defined as previously identified adiponectin-inducing alleles 9, [12][13][14][15] . Multiple linear regression analyses were performed to test the independent effects of each allele from each SNP on adiponectin and metabolic syndrome traits, accounting for the effects of other variables [i.e., age, sex, body mass index (BMI), VFA, and SFA].…”

“…We selected three SNPs (rs3865188, rs4783244, and rs12051272) in the CDH13 gene that were recently identified by GWASs 9, [12][13][14][15] and constructed Invader probes (Third Wave Technologies, Madison, WI, USA) for these SNPs. The SNPs were genotyped using Invader assays, as previously described 23) , and used for analysis.…”

“…In parallel with an increase in visceral fat, circulating adiponectin levels decrease, causing insulin resistance, type 2 diabetes, and cardiovascular disease, thereby providing a critical link between visceral fat accumulation and metabolic syndrome [2][3][4][5][6][7][8] . However, in addition to visceral fat accumulation, genetic variations may affect adiponectin levels, as demonstrated in recent genome-wide association studies (GWASs) [9][10][11][12][13][14][15][16][17] . One of the most important genetic variations determining adiponectin levels is located in the cadherin 13 (CDH13) gene, which encodes an adiponectin receptor 18) .…”

CDH13 Genotype–Dependent Association of High–Molecular Weight Adiponectin With All-Cause Mortality: The J-SHIPP Study

“…The CDH13 gene encodes T-cadherin, a receptor for hexameric and high-molecular weight forms of adiponectin (HMWA) (16). Although earlier studies (17,18) and recent GWAS in European subjects (19,20) reported a strong susceptibility of SNPs in the ADIPOQ gene that encodes adiponectin, GWAS of adiponectin in East Asian subjects, namely Korean (15) and Japanese (21), identified SNPs in the CDH13 locus, such as rs4783244.…”

Genetic Determination of Serum Levels of Diabetes-Associated Adipokines

“…The association of SNPs in the CDH13 locus with plasma adiponectin levels was supported by further studies showing several signals depending on the investigated population, mainly Chinese and Japanese ( Table 2) [134][135][136][137]. The CDH13 promotor SNP rs12444338 G-allele was associated with increased promoter activity in a luciferase assay [134].…”