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Clinical and genetic factors predicting response to therapy in patients with Crohn's disease.

ABSTRACT: AIM: To identify clinical and/or genetic predictors of response to several therapies in Crohn's disease (CD) patients. METHODS: We included 242 patients with CD (133 females) aged (mean?±?standard deviation) 39?±?12 years and a disease duration of 12?±?8 years. The single-nucleotide polymorphisms (SNPs) studied were ABCB1 C3435T and G2677T/A, IL23R G1142A, C2370A, and G9T, CASP9 C93T, Fas G670A and LgC844T, and ATG16L1 A898G. Genotyping was performed with real-time PCR with Taqman probes. RESULTS: Older patients responded better to 5-aminosalicylic acid (5-ASA) and to azathioprine (OR 1.07, p?=?0.003 and OR 1.03, p?=?0.01, respectively) while younger ones responded better to biologicals (OR 0.95, p?=?0.06). Previous surgery negatively influenced response to 5-ASA compounds (OR 0.25, p?=?0.05), but favoured response to azathioprine (OR 2.1, p?=?0.04). In respect to genetic predictors, we observed that heterozygotes for ATGL16L1 SNP had a significantly higher chance of responding to corticosteroids (OR 2.51, p?=?0.04), while homozygotes for Casp9 C93T SNP had a lower chance of responding both to corticosteroids and to azathioprine (OR 0.23, p?=?0.03 and OR 0.08, p?=?0.02,). TT carriers of ABCB1 C3435T SNP had a higher chance of responding to azathioprine (OR 2.38, p?=?0.01), while carriers of ABCB1 G2677T/A SNP, as well as responding better to azathioprine (OR 1.89, p?=?0.07), had a lower chance of responding to biologicals (OR 0.31, p?=?0.07), which became significant after adjusting for gender (OR 0.75, p?=?0.005). CONCLUSIONS: In the present study, we were able to identify a number of clinical and genetic predictors of response to several therapies which may become of potential utility in clinical practice. These are preliminary results that need to be replicated in future pharmacogenomic studies.

SUBMITTER: Cravo M

PROVIDER: S-EPMC4040806 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Clinical and genetic factors predicting response to therapy in patients with Crohn's disease.

Cravo Marilia M Ferreira Paula P Sousa Patricia P Moura-Santos Paula P Velho Sonia S Tavares Lurdes L Deus João Ramos JR Ministro Paula P da Silva João Pereira JP Correia Luis L Velosa Jose J Maio Rui R Brito Miguel M

United European gastroenterology journal 20140201 1

<h4>Aim</h4>To identify clinical and/or genetic predictors of response to several therapies in Crohn's disease (CD) patients.<h4>Methods</h4>We included 242 patients with CD (133 females) aged (mean ± standard deviation) 39 ± 12 years and a disease duration of 12 ± 8 years. The single-nucleotide polymorphisms (SNPs) studied were ABCB1 C3435T and G2677T/A, IL23R G1142A, C2370A, and G9T, CASP9 C93T, Fas G670A and LgC844T, and ATG16L1 A898G. Genotyping was performed with real-time PCR with Taqman p ...[more]

PMID: 24918007

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Project description:The fecal microbiota is a rich source of biomarkers that have previously been shown to be predictive of numerous disease states. Less well studied is the effect of immunomodulatory therapy on the microbiota and its role in response to therapy. This study explored associations between the fecal microbiota and therapeutic response of Crohn's disease (CD) patients treated with ustekinumab (UST; Stelara) in the phase 2 CERTIFI study. Using stool samples collected over the course of 22 weeks, the composition of these subjects' fecal bacterial communities was characterized by sequencing the 16S rRNA gene. Subjects in remission could be distinguished from those with active disease 6 weeks after treatment using random forest models trained on subjects' baseline microbiota and clinical data (area under the curve [AUC] of 0.844, specificity of 0.831, sensitivity of 0.774). The most predictive operational taxonomic units (OTUs) that were ubiquitous among subjects were affiliated with Faecalibacterium and Escherichia or Shigella The median baseline community diversity in subjects in remission 6 weeks after treatment was 1.7 times higher than that in treated subjects with active disease (P = 0.020). Their baseline community structures were also significantly different (P = 0.017). Two OTUs affiliated with Faecalibacterium (P = 0.003) and Bacteroides (P = 0.022) were significantly more abundant at baseline in subjects who were in remission 6 weeks after treatment than those with active CD. The microbiota diversity of UST-treated clinical responders increased over the 22 weeks of the study, in contrast to nonresponsive subjects (P = 0.012). The observed baseline differences in fecal microbiota and changes due to therapeutic response support the potential for the microbiota as a response biomarker.IMPORTANCE CD is a global health concern, with increasing incidence and prevalence, causing large economic and health care impacts. Finding prognostic biomarkers that give clinicians the ability to identify patients more likely to respond to CD treatment at diagnosis will reduce the time subjects receive drugs that are unlikely to be beneficial. OTUs associated with remission after treatment induction, especially Faecalibacterium, could be biomarkers for successful UST treatment of anti-tumor necrosis factor alpha (anti-TNF-α) refractory CD patients. More broadly, these results suggest that the fecal microbiota could be a useful noninvasive biomarker for directing or monitoring the treatment of gastrointestinal diseases.

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Clinical and genetic factors predicting response to therapy in patients with Crohn's disease.

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Clinical and genetic factors predicting response to therapy in patients with Crohn's disease.

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