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.
Highlights
The relevance of the Cadherin-13 gene (CDH13; 1.2 Mb) in a wide spectrum of biomedical fields—oncology, neurology, cardiovascular physiology—was recognized over a decade ago (Takeuchi and Ohtsuki 2001)
Association testing was performed between the seven shared SNPs and DNA methylation levels at the 46 CpG sites/units measured in HYPertension in ESTonia (HYPEST)/Coronary Artery Disease in Czech study (CADCZ)
We hypothesized that the pleiotropy and heterogeneity of genetic associations in CDH13 with a number of cardiometabolic traits might reflect interplay of inter-individual differences in DNA methylation variation
Summary
The relevance of the Cadherin-13 gene (CDH13; 1.2 Mb) in a wide spectrum of biomedical fields—oncology, neurology, cardiovascular physiology—was recognized over a decade ago (Takeuchi and Ohtsuki 2001). Localized in membrane lipid rafts, T-cadherin functions in promoting survival, proliferation and migration of endothelial cells and in protecting cells from oxidative stress-induced apoptosis (Philippova et al 2009; Joshi et al 2005). In cardiovascular metabolism, it exhibits ligand-binding ability uncommon to classical cadherins, acting as the third receptor for high molecular weight (HMW) adiponectin and binding low-density lipoprotein (LDL) (Tkachuk et al 1998; Hug et al 2004). A considerable number of human cancer genomes are characterized by hypermethylated CDH13 promoter, and down-regulation of its transcription promotes tumor growth and invasiveness (Andreeva and Kutuzov 2010)
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