Integrins as Determinants of Genetic Susceptibility, Tumour Behaviour and Their Potential as Therapeutic Targets

1625 Genome-Wide Association Analysis and Replication In 810,625 Individuals Identifies Novel Therapeutic Targets for Varicose Veins

British Journal of Surgery ◽

10.1093/bjs/znab258.029 ◽

2021 ◽

Vol 108 (Supplement_6) ◽

Author(s):

W U l R Ahmed ◽

A Wiberg ◽

M Ng ◽

W Wang ◽

A Auton ◽

...

Keyword(s):

Genetic Susceptibility ◽

Varicose Veins ◽

Genetic Risk Score ◽

Personalised Medicine ◽

Therapeutic Targets ◽

Biological Pathways ◽

Genome Wide Association ◽

Uk Biobank ◽

Genome Wide ◽

Weighted Genetic Risk Score

Abstract Aim To elucidate the genetic architecture of varicose veins (VVs) and identify genes and biological pathways central to their pathobiology. Method We performed hitherto 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, Inc (total 135,514 VVs cases and 675,111 controls). Genes and biological pathways were prioritised using several bioinformatic approaches, and potential therapeutic targets were identified in the Open Targets Platform. A weighted genetic risk score (wGRS) for VVs was constructed to compare genetic susceptibility in surgical vs non-surgical VVs patients. Results 109 genome-wide significant (P ≤ 5 × 10-8) loci were identified in UK Biobank, 46 of which successfully replicated in the 23andMe cohort. Twenty-eight loci have not been previously reported. We mapped 237 genes to these loci, many of which are biologically relevant and tractable to therapeutic targeting or repurposing (notably VEGFA, COL27A1, EFEMP1, PPP3R1 and NFATC2). 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. The wGRS analysis demonstrated that VVs patients requiring surgery have a higher inherent genetic susceptibility than those managed non-surgically (P = 2.46 × 10−13). Conclusions This study has advanced our understanding of VVs pathobiology with the identification of several biologically plausible genes and pathways, many of which demonstrate strong therapeutic potential. The wGRS correlated with disease severity, representing a first step in personalised medicine approaches to VVs.

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1540 Genome-Wide Association Analysis In 401,583 Individuals Identifies Novel Therapeutic Targets for Haemorrhoids

British Journal of Surgery ◽

10.1093/bjs/znab258.056 ◽

2021 ◽

Vol 108 (Supplement_6) ◽

Author(s):

W U l R Ahmed ◽

A Wiberg ◽

M Ng ◽

N J Smart ◽

K T Zondervan ◽

...

Keyword(s):

Genetic Susceptibility ◽

Genome Wide Association Study ◽

Therapeutic Potential ◽

Genetic Risk Score ◽

Personalised Medicine ◽

Therapeutic Targets ◽

Biological Pathways ◽

Genome Wide Association ◽

Genome Wide ◽

Weighted Genetic Risk Score

Abstract Aim To elucidate the genetic architecture of haemorrhoids and identify genes and biological pathways central to their pathobiology. Method We report the first ever genome-wide association study of haemorrhoids in 31,652 cases and 369,931 controls from UK Biobank. Genes and biological pathways were prioritised using several bioinformatic approaches, and potential therapeutic targets were identified in the Open Targets Platform. A weighted genetic risk score (wGRS) for haemorrhoids was constructed to compare genetic susceptibility in surgical vs non-surgical haemorrhoids patients. Results Twelve novel genome-wide significant susceptibility loci were discovered to be associated with haemorrhoids. Seventeen genes were mapped to these loci, and gene sets in biological pathways relating to extracellular matrix regulation and TGF-β signalling were strongly implicated. Seven gene-products (41.2%) were predicted tractable to antibody and/or small molecule targeting, and three products (17.6%) have known pharmaceutical interactions (ACHE, ADRA2B, ELN). The wGRS analysis demonstrated that haemorrhoid patients requiring surgery have a higher inherent genetic susceptibility than those managed non-surgically (P = 4.58 × 10-27). Conclusions This study has advanced our understanding of haemorrhoids pathobiology with the identification of several biologically plausible genes and pathways, many of which demonstrate strong therapeutic potential. The wGRS correlated with disease severity, representing a first step in personalised medicine approaches to haemorrhoids.

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