Abstract
Chronic venous disease (CVD) is a multifactorial condition representing one of the most common disorders among populations of Western countries. The heritability of about 17% suggests genetic risk factors in CVD etiology. However, so far the genetic causes are unknown. We undertook the hitherto first genome-wide association study (GWAS) for CVD, analyzing more than 1.93 M SNPs in 4,942 German individuals, followed by replication in two independent German data sets. The combined analysis of discovery and replication stages (2,269 cases and 7,765 controls) yielded robust associations within the two genes EFEMP1 and KCNH8 (rs17278665, rs727139 with P < 5 × 10−8), and suggestive association within gene SKAP2 (rs2030136 with P < 5 × 10−7). Association signals of rs17278665 and rs727139 reside in regions of low linkage disequilibrium containing no other genes. Data from the ENCODE and Roadmap Epigenomics projects show that tissue specific marks overlap with the variants. SNPs rs17278665 and rs2030136 are known eQTLs. Our study demonstrates that GWAS are a valuable tool to study the genetic component of CVD. With our approach, we identified two novel genome-wide significant susceptibility loci for this common disease. Particularly, the extracellular matrix glycoprotein EFEMP1 is promising for future functional studies due to its antagonistic role in vessel development and angiogenesis.
Highlights
Many factors may increase risk for CVD, including age, female gender, pregnancy, hormonal changes, obesity and standing occupation and predispose individuals to the dilatation, elongation and tortuosity of the saphenous vein and its tributaries[7]
When checking for potential coding SNPs being highly correlated (r2 > 0.8 in 1000 Genomes European samples) with the three lead SNPs (Methods), we identified only one further intronic SNP at the EFEMP1 and KCNH8 loci, respectively
We performed to our knowledge the first genome-wide association study for CVD and identified three novel CVD susceptibility loci
Summary
Many factors may increase risk for CVD, including age, female gender, pregnancy, hormonal changes, obesity and standing occupation and predispose individuals to the dilatation, elongation and tortuosity of the saphenous vein and its tributaries[7]. The narrow-sense heritability (proportion of the phenotypic variance that is explained by additive genetic variance) of PVV and CVD has recently been estimated to equal 18.5% and 17.3%, respectively, in a large sample of affected nuclear families from Germany[4]. These heritability estimates suggest the existence of susceptibility genes, necessitating large systematic association studies. To further our understanding of the genetic etiology of CVD, we undertook the hitherto first genome-wide association study (GWAS) for this multifactorial condition comprising 10,034 individuals in total
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
