Genome-wide scan identifies CDH13 as a novel susceptibility locus contributing to blood pressure determination in two European populations

Abstract

Hypertension is a complex disease that affects a large proportion of adult population. Although approximately half of the inter-individual variance in blood pressure (BP) level is heritable, identification of genes responsible for its regulation has remained challenging. Genome-wide association study (GWAS) is a novel approach to search for genetic variants contributing to complex diseases. We conducted GWAS for three BP traits [systolic and diastolic blood pressure (SBP and DBP); hypertension (HYP)] in the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) S3 cohort (n = 1644) recruited from general population in Southern Germany. GWAS with 395 912 single nucleotide polymorphisms (SNPs) identified an association between BP traits and a common variant rs11646213 (T/A) upstream of the CDH13 gene at 16q23.3. The initial associations with HYP and DBP were confirmed in two other European population-based cohorts: KORA S4 (Germans) and HYPEST (Estonians). The associations between rs11646213 and three BP traits were replicated in combined analyses (dominant model: DBP, P = 5.55 × 10–5, effect –1.40 mmHg; SBP, P = 0.007, effect –1.56 mmHg; HYP, P = 5.30 × 10−8, OR = 0.67). Carriers of the minor allele A had a decreased risk of hypertension. A non-significant trend for association was also detected with severe family based hypertension in the BRIGHT sample (British). The novel susceptibility locus, CDH13, encodes for an adhesion glycoprotein T-cadherin, a regulator of vascular wall remodeling and angiogenesis. Its function is compatible with the BP biology and may improve the understanding of the pathogenesis of hypertension.

Codon 72 polymorphism (rs1042522) of TP53 is associated with changes in diastolic blood pressure over time

“…[15][16][17][18][19][20][21][22][23] As these studies have a cross-sectional design, it is not possible to examine the effect of a SNP on development of a trait. We suggest that rs1042522 has a role in the development of DBP and waist circumference during ageing and therefore, a SNP effect alone will be less informative compared with a SNP*time interaction in this case.…”

Joint detection of association, imprinting and maternal effects using all children and their parents

“…For example, SNP rs11149562 (P ¼ 2.24 Â 10 À5 ), residing in the intron region of gene CDH13 on chromosome 16, has been reported to be a candidate hypertensive susceptibility gene in two European populations, and is associated with both longterm systolic blood pressure and diastolic blood pressure. 19,20 In fact, CDH13 encodes for an adhesion glycoprotein T-cadherin, which is a regulator of vascular wall remodeling and angiogenesis, and is compatible with the blood pressure biology. Another SNP, rs7559838 (P ¼ 1.32 Â 10 À5 ), located in the intron region of gene HPCAL1 on chromosome 2, has also been linked to hypertensive phenotype in the Japanese population.…”

Genetic basis of hypertension for the development of tailored medicine

“…This gene encodes for an adhesion glycoprotein QJ;T-cadherin, a regulator of vascular wall remodeling and angiogenesis. 38 The significant association was reconfirmed in KORA S4 (Germans) and HYPEST (Estonians), and a similar trend was observed in BRIGHT (British). It is interesting that T-cadherin is also a receptor for the hexameric and high-molecular-weight species of adiponectin, but not for the trimeric or globular species.…”