A Genetic Variant in the BCL2 Gene Associates with Adalimumab Response in Hidradenitis Suppurativa Clinical Trials and Regulates Expression of BCL2.

Abstract

Hidradenitis suppurativa is a chronic skin disease with a significant genetic component and prevalence from 0.5% to 4%. Adalimumab is the only treatment approved by either the European Medicines Agency or the U.S. Food and Drug Administration for the management of moderate to severe hidradenitis suppurativa. To identify genetic variants associated with adalimumab response, we performed a genome-wide association study (GWAS) from the most extensive two phase 3 hidradenitis suppurativa clinical trials (PIONEER I and II) to date. Through direct genotyping and imputation, we tested almost 7 million genetic variants with minor allele frequency > 5% and identified one single linkage disequilibrium block, located in the intron of the BCL2 gene, which reached genome-wide significance (lead single-nucleotide polymorphism, rs59532114; P = 2.35E-08). Bioinformatic analysis and functional genomics experiments suggested a correlation of the most strongly associated single-nucleotide polymorphism minor allele with increased BCL2 gene and protein expressions in hair follicle tissues. In reciprocal knockdown experiments, we found that BCL2 is down-regulated by TNF inhibition. These results highlight a pathway that involves BCL2 in response to adalimumab. Further work is required to determine how this pathway influences adalimumab effectiveness in patients with hidradenitis suppurativa.

• Authors: Mohan Liu, Jacob Degner, Robert W Georgantas, Ahmed Nader, Nael M Mostafa, Henrique D Teixeira, David A Williams, Robert S Kirsner, Anna J Nichols, Justin Wade Davis, Jeffrey F Waring
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 140 Issue 3 Pg. 574-582.e2 (03 2020) ISSN: 1523-1747 [Electronic] United States
• PMID: 31465739 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Anti-Inflammatory Agents
• BCL2 protein, human
• Proto-Oncogene Proteins c-bcl-2
• TNF protein, human
• Tumor Necrosis Factor-alpha
• Adalimumab

Topics

• Adalimumab (pharmacology, therapeutic use)
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Clinical Trials, Phase III as Topic
• Computational Biology
• Datasets as Topic
• Down-Regulation (drug effects)
• Drug Resistance (genetics)
• Gene Frequency
• Gene Knockdown Techniques
• Genome-Wide Association Study
• Hair Follicle (pathology)
• Hidradenitis Suppurativa (drug therapy, genetics, pathology)
• Humans
• Keratinocytes
• Polymorphism, Single Nucleotide
• Primary Cell Culture
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• Quantitative Trait Loci (genetics)
• Signal Transduction (drug effects)
• Treatment Outcome
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, metabolism)
• Up-Regulation (genetics)