AUTHOR=Walczak Michal , Lykowska-Szuber Liliana , Plucinska Marianna , Stawczyk-Eder Kamila , Zakerska-Banaszak Oliwia , Eder Piotr , Krela-Kazmierczak Iwona , Michalak Michal , Zywicki Marek , Karlowski Wojciech M. , Szalata Marlena , Dobrowolska Agnieszka , Slomski Ryszard , Skrzypczak-Zielinska Marzena 

TITLE=Is Polymorphism in the Apoptosis and Inflammatory Pathway Genes Associated With a Primary Response to Anti-TNF Therapy in Crohn’s Disease Patients?

JOURNAL=Frontiers in Pharmacology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2020.01207

DOI=10.3389/fphar.2020.01207

ISSN=1663-9812

ABSTRACT=<p>Anti-tumor necrosis factor (TNF) therapy is used for the induction and maintenance of remission in Crohn’s disease (CD) patients. However, primary nonresponders to initial treatment constitute 20%–40% of cases. The causes of this phenomenon are still unknown. In this study, we aimed to determine the genetic predictors of the variable reactions of CD patients to anti-TNF therapy. Using long-range PCR libraries and the next-generation sequencing (NGS) method, we performed broad pharmacogenetic studies including a panel of 23 genes (<italic>TNFRSF1A</italic>, <italic>TNFRSF1B</italic>, <italic>CASP9</italic>, <italic>FCGR3A</italic>, <italic>LTA</italic>, <italic>TNF</italic>, <italic>FAS</italic>, <italic>ADAM17</italic>, <italic>IL17A</italic>, <italic>IL6</italic>, <italic>MMP1</italic>, <italic>MMP3</italic>, <italic>S100A8</italic>, <italic>S100A9</italic>, <italic>S100A12</italic>, <italic>TLR2</italic>, <italic>TLR4</italic>, <italic>TLR9</italic>, <italic>CD14</italic>, <italic>IL23R</italic>, <italic>IL23</italic>, <italic>IL1R</italic>, and <italic>IL1B</italic>) in a group of 107 diagnosed and clinically characterized CD patients following anti-TNF therapy. In the studied group, we indicated, in total, 598 single nucleotide variants for all analyzed genomic targets. Twelve patients (11.2%) did not respond to the induction therapy, which was associated with alleles in 11 <italic>loci</italic> located in <italic>FCGR3A</italic> (rs7539036, rs6672453, rs373184583, and rs12128686), <italic>IL1R</italic> (rs2041747), <italic>TNFRSF1B</italic> (rs5746053), <italic>IL1B</italic> (rs1071676, rs1143639, rs1143637, and rs1143634), and <italic>FAS</italic> (rs7896789) genes. After multiple comparison corrections, the results were not statistically significant, however for nonresponders the alleles distribution for those <italic>loci</italic> presented large differences and specified scheme compared to responders and populations. These findings require further investigation in an independent larger cohort before introducing them for a clinical setting, however, we identified an interesting direction. Polymorphism of the <italic>FCGR3A</italic>, <italic>IL1R</italic>, <italic>TNFRSF1B</italic>, <italic>IL1B</italic>, and <italic>FAS</italic> genes could be a predictor of the primary response to anti-TNF therapy in CD patients.</p>