A GENETIC VARIANT IN THE BCL2 GENE ASSOCIATES WITH ADALIMUMAB RESPONSE IN HIDRADENITIS SUPPURATIVA CLINICAL TRIALS AND REGULATES EXPRESSION OF BCL2

Abstract Hidradenitis Suppurativa (HS) is a chronic skin disease with strong genetic component and prevalance from 0.5% to 4%. Adalimumab is the only treatment approved by either the European Medicines Agency (EMA) or the US Food or Drug Administration (FDA) for the management of moderate-to-severe HS. To identify genetic variants associated with adalimumab response, we performed a genome-wide association study (GWAS) from the largest two Phase 3 HS clinical trials (PIONEER I and II) to date. Through direct genotyping and imputation, we tested almost 7 million genetic variants with MAF > 5% and identified one single linkage disequilibrium (LD) block, located in the intron of the BCL2 gene, which reached genome-wide significance (lead single-nucleotide polymorphism [SNP] rs 59532114; p=2.35E-08). Bioinformatic analysis and functional genomics experiments suggested correlation of the most strongly associated SNP minor allele with increased BCL2 gene and protein expression in hair follicle tissues. In reciprocal knockdown experiments, we found that BCL2 is down-regulated by TNF inhibition. These results highlight to our knowledge previously unreported pathway that involves BCL2 in response to adalimumab. Further work is required to determine how this pathway influences adalimumab effectiveness in patients suffering with HS.