Systematic identification of clinically relevant genetic risk factors for chronic venous disease

• Applicant: Eva Ellinghaus, Ph.D.
• Subject Area: Cardiac and Vascular Surgery ; Epidemiology and Medical Biometry/Statistics ; Human Genetics
• Term: since 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 406697368

Chronic venous disease (CVD) is a multifactorial condition with a prevalence in Germany estimated at about 31%. With an estimated cost of up to 2% of the total health-care budget of all Western countries, the financial burden of CVD treatment on the health-care system is immense. In addition to several factors like age, gender, obesity and standing occupation, evidence of a genetic component for CVD has been provided by twin studies and reports on familial clustering with an estimated heritability of 17.3%. Nevertheless, despite its major socioeconomic impact, only one genome-wide association study (GWAS) for CVD has been published to date and the genetic background of this disease still remains poorly understood. Therefore, there is considerable interest in a hypothesis-free genome-wide approach such as a GWAS in a large case-control sample to identify the genetic susceptibility factors for CVD in order to reveal critical biological pathways and translate genetic findings into improved disease treatment and prevention. To enable fundamental clinically relevant progress for CVD, the applicant proposes to perform a GWAS with 3,228 CVD cases and 5,232 controls using Illumina´s global screening array (GSA) in order to detect and characterize common and rare genetic risk variants and genes associated with CVD. The GSA array covers 600,000 single nucleotide polymorphism (SNP) markers for maximized genomic coverage and imputation accuracy in addition to 100,000 predictive clinical markers and provides a superior cost-performance ratio compared to previous GWAS arrays. State-of-the-art association analyses will be performed for a near complete catalogue of variants with a frequency >0.1% in European populations to identify statistically convincing causal genetic variants and to provide a powerful substrate for experimental elucidation of disease mechanisms. For a comprehensive investigation of the genetic basis of CVD, the applicant will conduct high-resolution fine-mapping to single variant resolution for identified risk loci including functional in silico annotation of associated variants, pathway and genomic annotation enrichment analysis, pathway network analysis and genetically regulated expression analysis to gain first insight into the genetic etiology of CVD. Basic experimental functional follow-up studies, e.g. screening for further mutations at associated genes or determination of transcript expression in different tissues will be performed, depending on the nature of variants and/or associated pathways. Throughout the duration of the project patient recruitment will be performed to enable an independent replication study. Furthermore, a “Preliminary Application” to obtain GWAS data of max. 500,000 study participants (incl. phenotype information about presence of varicose veins) for replication/meta-analysis purposes has been approved by the UK Biobank and it is expected that the “Main Application” will be approved as well.

• DFG Programme: Research Grants