Pharmacogenetic markers of response to drugs used in the management of Inflammatory Bowel Disease

摘要

Background and Aims: The inflammatory bowel diseases (IBD) are chronic diseases that affect populations worldwide and impart considerable morbidity to those affected. Immunosuppression in IBD is effective but limited by side effects and non-response. We aimed to identify pharmacogenetic markers of response to commonly used immunosuppressive medication in these patients.Methods: The influence of MTHFR 677CT, MTHFR 1298AT, ATIC 347CG, TSER *2/*3 tandem repeat, TYMS 3’-UTR 6 bp insertion/deletion, SLC19A1 80GA, AOX 3404AG polymorphisms, 14bp ins/del polymorphism in the HLA-G gene and the IL-10 -1082AG, -819CT and -592CA promoter SNPs were investigated on clinical response and side effect rates in 201 patients with Inflammatory Bowel Disease (IBD) treated with methotrexate (MTX). The HLA-G 14 bp ins/del polymorphism was correlated with azathioprine (AZA) response in 97 IBD patients. The IL-10 -1082AG, -819CT and -592CA promoter SNPs on chromosome 1 were examined for an influence on the effect of the 14bp ins/del polymorphism in this group. The 14bp ins/del polymorphism was examined for an influence on susceptibility to IBD in 3148 individuals compared with 1330 normal controls. Stimulated PBMC from 14 normal individuals were incubated with MTX and 6-MP and expression levels of soluble HLA-G and IL-10 were correlated with genotype.Results: A small positive correlation was seen for the MTHFR677TT genotype for clinical response and for the ATIC347GG for intolerance to MTX. The 14bp ins/del polymorphism strongly predicted clinical response to MTX (p=0.0016). The same influence was seen in 97 IBD patients treated with azathioprine (AZA) (p=0.001) and neither of these effects were affected by variant IL-10 promoter haplotypes. The described polymorphism did not influence susceptibility to IBD. Individuals with the 14bp del/del polymorphism expressed more soluble HLA-G after incubation with 6-MP (p=0.02) and MTX than carriers of the insertion allele. A dose effect was evident and carriers of the high producer IL-10 GCC promoter haplotype expressed significantly more IL-10 when incubated with 6-MP (p=0.04). This provides functional correlation of the genetic effect.Conclusion: HLA-G genotype maybe a strong and predictor of response to MTX and AZA in IBD patients. These are preliminary findings and need replication in prospective studies.