Crohn's disease is complex chronic inflammatory bowel disease that can affect the entire digestive tract. As an autoimmune disease, the exact pathogenesis is poorly understood and is a product of several genetic, immunological, and environmental factors. Diagnosis is made with laboratory and endoscopic methods. Treatment includes a wide variety of drug options. Ustekinumab, a novel medication, is a monoclonal antibody that binds to the p40 subunit shared by interleukin 12 and interleukin 23, thus preventing pro-inflammatory processes in the cell. It is effective at inducing and maintaining remission, and so serves as an alternative to anti-tumor necrosis factor drugs. However, some patients do not achieve a satisfactory response to the treatment. The aim of our study was to improve the understanding of the association between gene polymorphisms in IL12B, FCGR2A in FCGR3A and response to ustekinumab treatment in Crohn's disease. First, we isolated DNA from the whole blood of 57 patients and genotyped it using real time polymerase chain reaction and hydrolysis probes. In addition to patients’ genotypes, we collected data of patients’ demographic, biochemical and clinical characteristics, as well as recorded their biochemical and endoscopic markers of response to treatment. Subsequently, we statistically evaluated the association between patients’ characteristics and their response to treatment, For IL12B rs3212227, we observed two relationships: a worse treatment response associated with wild type homozygous genotype (AA) when comparing fecal calprotectin concentration to the other two genotypes combined (p=0,088); and a worse treatment response associated with mutated homozygous genotype (CC) when comparing SES-CD scoring to the other two genotypes combined (p=0,043). For IL12B rs3213094 the same relationships were found: a worse treatment response, associated with wild type homozygous genotype (CC) when comparing fecal calprotectin concentration to the other two genotypes combined (p=0,088); and a worse treatment response associated with mutated homozygous genotype (TT) when comparing SES-CD scoring to the other two genotypes combined (p=0,043). For IL12B rs6887695, we observed the association between heterozygous genotype (GC) and better treatment response compared to both genotypes individually based on the fecal calprotectin concentration (p=0,012) and higher proportion of biochemical response (p=0,010). We also observed a worse response of wild type homozygous genotype (GG) compared to the other two genotypes combined based on the fecal calprotectin concentration (p=0,076) and a lower proportion of biochemical response (p=0,09). For FCGR2A rs1801274 we observed no association with treatment response. Similarly we observed no association for FCGR3A rs396991 with treatment response, however the mutated homozygous genotype (CC) had a nonsignificant trend of a lower fecal calprotectin concentration at baseline compared to the other two genotypes combined (p=0,059). Modeling with multivariable linear and logistic regression showed the association between treatment response and the following variables: age, sex, heterozygous genotype FCGR3A, heterozygous genotype IL12B rs6887695, mutated homozygous genotype IL12B rs3212227 and rs3213094, bio naivety and ulcers at baseline. Our result indicate that more studies with larger sample size are necessary to clarify the clinical relevance of genetic polymorphisms in ustekinumab treatment, and we suggest that further reasearch could be focused especially on IL12B rs3212227 and IL12B rs6887695 polymorphisms while considering the effect of HLA-Cw6 haplotype as well.
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