CDH13 promoter SNPs with pleiotropic effect on cardiometabolic parameters represent methylation QTLs

Abstract

CDH13 encodes T-cadherin, a receptor for high molecular weight (HMW) adiponectin and low-density lipoprotein, promoting proliferation and migration of endothelial cells. Genome-wide association studies have mapped multiple variants in CDH13 associated with cardiometabolic traits (CMT) with variable effects across studies. We hypothesized that this heterogeneity might reflect interplay with DNA methylation within the region. Resequencing and EpiTYPER™ assay were applied for the HYPertension in ESTonia/Coronary Artery Disease in Czech (HYPEST/CADCZ; n = 358) samples to identify CDH13 promoter SNPs acting as methylation Quantitative Trait Loci (meQTLs) and to investigate their associations with CMT. In silico data were extracted from genome-wide DNA methylation and genotype datasets of the population-based sample Estonian Genome Center of the University of Tartu (EGCUT; n = 165). HYPEST–CADCZ meta-analysis identified a rare variant rs113460564 as highly significant meQTL for a 134-bp distant CpG site (P = 5.90 × 10−6; β = 3.19 %). Four common SNPs (rs12443878, rs12444338, rs62040565, rs8060301) exhibited effect on methylation level of up to 3 neighboring CpG sites in both datasets. The strongest association was detected in EGCUT between rs8060301 and cg09415485 (false discovery rate corrected P value = 1.89 × 10−30). Simultaneously, rs8060301 showed association with diastolic blood pressure, serum high-density lipoprotein and HMW adiponectin (P < 0.005). Novel strong associations were identified between rare CDH13 promoter meQTLs (minor allele frequency <5 %) and HMW adiponectin: rs2239857 (P = 5.50 × 10−5, β = −1,841.9 ng/mL) and rs77068073 (P = 2.67 × 10−4, β = −2,484.4 ng/mL). Our study shows conclusively that CDH13 promoter harbors meQTLs associated with CMTs. It paves the way to deeper understanding of the interplay between DNA variation and methylation in susceptibility to common diseases.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-014-1521-6) contains supplementary material, which is available to authorized users.

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

“…One of the mechanism through which CDH13 SNPs may affect the expression of the CDH13 gene was reported by Putku et al 28) , who showed that some of SNPs around the CpG island within the regulatory region of the CDH13 gene affect the methylation levels of the gene region. Adiponectin-inducing alleles of SNPs (rs8060301 and rs12444338) were related to hypermethylation within the CpG island, which would reduce the expression of CDH13.…”

Genetic Determination of Serum Levels of Diabetes-Associated Adipokines

“…Four common variants (rs12443878 C/A, rs12444338 G/T, rs62040565 C/T, and rs8060301 A/T) exhibited effects on methylation levels of up to 3 CpG sites located 19-167,744 bp from the respective SNPs. SNP rs8060301 was also associated with highmolecular-weight adiponectin levels [184]. Rs8060301 is in LD with the previously described SNP rs4783244.…”

“…A recent study by Putku et al showed that the CDH13 promoter harbors methylation quantitative trait loci (meQTLs) associated with cardiometabolic traits [184]. Four common variants (rs12443878 C/A, rs12444338 G/T, rs62040565 C/T, and rs8060301 A/T) exhibited effects on methylation levels of up to 3 CpG sites located 19-167,744 bp from the respective SNPs.…”

“…Rs8060301 is in LD with the previously described SNP rs4783244. Since rs8060301 is located at the strongest binding site of RNA polymerase II (Pol2) within the CDH13 promoter, it is speculated that this SNP acts as a causal variant that directly affects gene expression driving the associations with metabolic phenotypes [184]. Finally, two rare CDH13 promoter meQTLs were associated with HMW adiponectin (rs2239857 C/G, rs77068073 C/T).…”

Impact of SNPs on CpG Islands in the MYC and HRAS oncogenes and in a wide variety of tumor suppressor genes: A multi-cancer approach

“…There have been numerous reports of SNPs affecting the hypermethylation of proximal and trans-gene CpG islands, [2][3][4][5][6] Table 3. Allele frequencies for the non-hg19 SNP alleles that occur most frequently in the indicated data sets and that create or eliminate CpG's.…”