title: Genome-wide association analysis for chronic venous disease identifies EFEMP1 and KCNH8 as susceptibility loci.
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.
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Ellinghaus
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Ellinghaus
authors.affiliation: Capio Mosel-Eifel-Clinic, 56864 Bad Bertrich, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Krusche
authors.affiliation: Capio Mosel-Eifel-Clinic, 56864 Bad Bertrich, Germany.
authors.forename: Aljoscha
authors.initials: A
authors.lastname: Greiner
authors.affiliation: Department of General Medicine, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Schreiber
authors.affiliation: Department of General Medicine, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
authors.forename: Susanna
authors.initials: S
authors.lastname: Nikolaus
authors.affiliation: Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.affiliation: Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.|Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, 80539 Munich, Germany.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Strauch
authors.affiliation: PopGen Biobank, Institute of Epidemiology, University Hospital Schleswig-Holstein, 24105 Kiel, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Lieb
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany.
authors.forename: Philip
authors.initials: P
authors.lastname: Rosenstiel
authors.affiliation: Capio Mosel-Eifel-Clinic, 56864 Bad Bertrich, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Frings
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Fiebig
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany.|Department of General Medicine, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics*; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D034081:Wasting Disease, Chronic / Q000235:genetics*; D055815:Young Adult
chemical_list: C119630:EFEMP1 protein, human; D051638:Ether-A-Go-Go Potassium Channels; D016326:Extracellular Matrix Proteins