Pharmacogenomic Landscape of Variants Affecting Response to TNF Inhibitors in the Qatari Population

Abstract

Autoimmune diseases are one of the leading causes of mortality and morbidity worldwide with a substantial economic burden. Tumor necrosis factor (TNF-α) alpha is an important cytokine that frequently contributes to autoimmune disease's pathogenicity. Therefore, TNF inhibitors are widely used to treat several autoimmune diseases, including arthritis and inflammatory bowel disease. However, 40% of the patients do not respond positively when treated with TNF inhibitors. Several pharmacogenomic variants have been identified affecting response to these drugs. However, the distribution of these variants in the Qatari population is unknown. To uncover the pharmacogenomics landscape of genetic variants associated with TNF inhibitors in the Qatari people, we evaluated the prevalence of known variants and identified novel variants in 881 genes associated with TNF inhibitors, TNF signaling pathways and TNF co-expression modules. Furthermore, the variability in the allele frequency distribution of pharmacogenetic variants in Qataris and other world populations was compared. We observed a high frequency of IL10 and IL1B gene variants, which affect both the positive and negative responses to etanercept and infliximab. Additionally, structural, and functional consequences of known and novel variants were predicted. We identified a novel deleterious missense variant p. (Pro88Ser) in the trimer region of TNF, increasing the binding affinity of TNFR1 with TNF. We hypothesize that such variants could reduce TNF-inhibitor response in patients with autoimmune disorders. The findings of this study provide an avenue for the implementation of pharmacogenomic testing and precision medicine in Qatar.

Date of Award	2022
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences