ABSTRACT
Tumor necrosis factor α inhibitors (anti-TNF) have improved treatment of several complex diseases, including Crohn's disease (CD). However, the effect varies and approximately one-third of the patients do not respond. Since blood parameters as well as genetic factors have shown a great potential to predict response during treatment, the aim of the study was to evaluate response to anti-TNF treatment with adalimumab (ADA) between genes HFE and TF and haematological parameters in Slovenian refractory CD patients. Single nucleotide polymorphisms (SNPs) rs1799852 in gene TF and rs2071303 in gene HFE were genotyped in 68 refractory CD patients for which response has been measured using inflammatory bowel disease questionnaire (IBDQ) index. Haematological parameters and IBDQ index were determined before therapy and after 4, 12, 20 and 30 weeks. We found novel strong association between SNP rs2071303 in gene HFE and response to ADA treatment, particularly patients with G allele comparing to A allele had better response after 20 weeks (p = 0.008). Further, we found strong association between transferrin level at baseline and treatment response after 12, 20 and 30 weeks, where average transferrin level before therapy was lower in responders (2.38 g/L) compared to non-responders (2.89 g/L, p = 0.005). Association was found between transferrin level in week 30 and SNP rs1799852 (p = 0.023), and between MCHC level before treatment and SNP rs2071303 (p = 0.007). Our results suggest that SNP in gene HFE as well as haematological markers serve as promising prognostic markers of response to anti-TNF treatment in CD patients.
Subject(s)
Adalimumab/therapeutic use , Crohn Disease/drug therapy , Hemochromatosis Protein/genetics , Polymorphism, Single Nucleotide , Transferrin/genetics , Crohn Disease/genetics , Crohn Disease/metabolism , Gene Expression Regulation/drug effects , Genetic Markers , Genotype , Humans , Slovenia , Transferrin/metabolism , Treatment OutcomeABSTRACT
Crohn's disease is often treated with the anti-tumor necrosis factor-α drug adalimumab. However, about 20%-40% of patients do not display adequate therapeutic response. We prospectively evaluated, during a routine therapy of Crohn's disease patients, the candidate autophagy-related genes ATG12 and ATG5 and the inflammation-related genes NFKB1, NFKBIA, and CRP as potential predictors of adalimumab treatment response (pharmacodynamics). The associations of haplotypes and SNPs in these genes with response to drug therapy, biochemical parameters, and body mass were determined at baseline and after 4, 12, 20, and 30 weeks of therapy. Association analysis showed that haplotypes defined with the SNPs rs9373839 and rs510432 in ATG5 gene were significantly associated with positive response to therapy (p < 0.002). In addition, allele C and genotypes CC and CT of the rs1130864 in the CRP gene were positively associated with therapeutic response (p < 0.002). To the best of our knowledge, this is the first report that supports the association of SNPs in ATG5 and CRP genes with response to adalimumab therapy in Crohn's disease. Further study of these biological pathways in larger and independent clinical samples is warranted as novel streams of research on precision medicine and diagnostics for Crohn's disease.
Subject(s)
Adalimumab/therapeutic use , Anti-Inflammatory Agents/therapeutic use , Autophagy-Related Protein 5/genetics , Crohn Disease/genetics , Polymorphism, Single Nucleotide/genetics , Adolescent , Adult , Child , Crohn Disease/drug therapy , Female , Genetic Association Studies , Humans , Male , Middle Aged , Models, Statistical , Pharmacogenetics , Precision Medicine , Prospective Studies , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Young AdultABSTRACT
AIM: To see if SNPs could help predict response to biological therapy using adalimumab (ADA) in Crohn's disease (CD). MATERIALS & METHODS: IBDQ index and CRP levels were used to monitor therapy response. We genotyped 31 CD-associated genes in 102 Slovenian CD patients. RESULTS: The strongest association for treatment response defined as decrease in CRP levels was found for ATG16L1 SNP rs10210302. Additional SNPs in 7 out of 31 tested CD-associated genes (PTGER4, CASP9, IL27, C11orf30, CCNY, IL13, NR1I2) showed suggestive association with ADA response. CONCLUSION: Our results suggest ADA response in CD patients is genetically predisposed by SNPs in CD risk genes and suggest ATG16L1 as most promising candidate gene for drug response in ADA treatment. Original submitted 24 September 2014; Revision submitted 1 December 2014.
