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

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...

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Autores principales: Putku, Margus, Kals, Mart, Inno, Rain, Kasela, Silva, Org, Elin, Kožich, Viktor, Milani, Lili, Laan, Maris
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4318987/
https://www.ncbi.nlm.nih.gov/pubmed/25543204
http://dx.doi.org/10.1007/s00439-014-1521-6
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author Putku, Margus
Kals, Mart
Inno, Rain
Kasela, Silva
Org, Elin
Kožich, Viktor
Milani, Lili
Laan, Maris
author_facet Putku, Margus
Kals, Mart
Inno, Rain
Kasela, Silva
Org, Elin
Kožich, Viktor
Milani, Lili
Laan, Maris
author_sort Putku, Margus
collection PubMed
description 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 MATERIAL: The online version of this article (doi:10.1007/s00439-014-1521-6) contains supplementary material, which is available to authorized users.
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spelling pubmed-43189872015-02-10 CDH13 promoter SNPs with pleiotropic effect on cardiometabolic parameters represent methylation QTLs Putku, Margus Kals, Mart Inno, Rain Kasela, Silva Org, Elin Kožich, Viktor Milani, Lili Laan, Maris Hum Genet Original Investigation 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 MATERIAL: The online version of this article (doi:10.1007/s00439-014-1521-6) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2014-12-28 2015 /pmc/articles/PMC4318987/ /pubmed/25543204 http://dx.doi.org/10.1007/s00439-014-1521-6 Text en © The Author(s) 2014 https://creativecommons.org/licenses/by/4.0/ Open AccessThis article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.
spellingShingle Original Investigation
Putku, Margus
Kals, Mart
Inno, Rain
Kasela, Silva
Org, Elin
Kožich, Viktor
Milani, Lili
Laan, Maris
CDH13 promoter SNPs with pleiotropic effect on cardiometabolic parameters represent methylation QTLs
title CDH13 promoter SNPs with pleiotropic effect on cardiometabolic parameters represent methylation QTLs
title_full CDH13 promoter SNPs with pleiotropic effect on cardiometabolic parameters represent methylation QTLs
title_fullStr CDH13 promoter SNPs with pleiotropic effect on cardiometabolic parameters represent methylation QTLs
title_full_unstemmed CDH13 promoter SNPs with pleiotropic effect on cardiometabolic parameters represent methylation QTLs
title_short CDH13 promoter SNPs with pleiotropic effect on cardiometabolic parameters represent methylation QTLs
title_sort cdh13 promoter snps with pleiotropic effect on cardiometabolic parameters represent methylation qtls
topic Original Investigation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4318987/
https://www.ncbi.nlm.nih.gov/pubmed/25543204
http://dx.doi.org/10.1007/s00439-014-1521-6
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