A Prospective Pharmacogenomic Study of Crohn's Disease Patients during Routine Therapy with Anti-TNF-α Drug Adalimumab: Contribution of ATG5, NFKB1, and CRP Genes to Pharmacodynamic Variability.
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.
1 Centre for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor , Maribor, Slovenia .
Matjaž
M
Deželak
1 Centre for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor , Maribor, Slovenia .|2 Laboratory for Biochemistry, Molecular Biology and Genomics, Faculty for Chemistry and Chemical Engineering, University of Maribor , Maribor, Slovenia .
Katja
K
Repnik
3 University Medical Centre Maribor , Maribor, Slovenia .
Silvo
S
Koder
4 University Medical Centre Ljubljana , Ljubljana, Slovenia .
Ivan
I
Ferkolj
1 Centre for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor , Maribor, Slovenia .|2 Laboratory for Biochemistry, Molecular Biology and Genomics, Faculty for Chemistry and Chemical Engineering, University of Maribor , Maribor, Slovenia .
Uroš
U
Potočnik
D000068879:Adalimumab / Q000627:therapeutic use*; D000293:Adolescent; D000328:Adult; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D000071187:Autophagy-Related Protein 5 / Q000235:genetics*; D002648:Child; D003424:Crohn Disease / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D057285:Precision Medicine; D011446:Prospective Studies; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D055815:Young Adult
C502778:ATG5 protein, human; D000893:Anti-Inflammatory Agents; D000071187:Autophagy-Related Protein 5; D014409:Tumor Necrosis Factor-alpha; D000068879:Adalimumab