Genome-wide association analysis and replication in 810,625 individuals identifies novel therapeutic targets for varicose veins
Ahmed W-U-R., Wiberg A., Ng M., Wang W., Auton A., Lee R., Handa A., Zondervan KT., Furniss D.
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Varicose veins (VVs) affect one-third of Western society, with a significant subset of patients developing venous ulceration, and ongoing management of venous leg ulcers costing around $14.9 billion annually in the USA. There is no current medical management for VVs, with approaches limited to compression stockings, ablation techniques, or open surgery for more advanced disease. A significant proportion of patients report a positive family history, and heritability is ~17%, suggesting a strong genetic component. We aimed to identify novel therapeutic targets by improving our understanding of the aetiopathology and genetic architecture of VVs.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We performed the largest two-stage genome-wide association study of VVs in 401,656 subjects from UK Biobank, and replication in 408,969 subjects from 23andMe (total 135,514 varicose veins cases and 675,111 controls). We constructed a genetic risk score for VVs to investigate its use as a prognostic tool. Genes and pathways were prioritised using a suite of bioinformatic tools, and therapeutic targets identified using the Open Targets Platform.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>We discovered 49 signals at 46 susceptibility loci associated with VVs, including 29 previously unreported genetic associations (28 susceptibility loci). We demonstrated that patients with VVs requiring surgery have a higher genetic risk score than those managed non-surgically. We map 237 genes to these loci, many of which are biologically relevant and tractable to therapeutic targeting or repurposing (notably <jats:italic>VEGFA</jats:italic>, <jats:italic>COL27A1</jats:italic>, <jats:italic>EFEMP1</jats:italic>, <jats:italic>PPP3R1</jats:italic> and <jats:italic>NFATC2</jats:italic>). Tissue enrichment analyses implicated vascular tissue, and several genes were enriched in biological pathways relating to extracellular matrix biology, inflammation, angiogenesis, lymphangiogenesis, vascular smooth muscle cell migration, and apoptosis.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Genes and pathways identified represent biologically plausible contributors to the pathobiology of VVs, identifying promising candidates for further investigation of venous biology and potential therapeutic targets. We have provided the proof-of-principle that genetic risk score correlates with disease severity, which represents a first step in personalised medicine approaches to varicose veins.</jats:p></jats:sec>