Novel pharmacogenetic markers for treatment outcome in azathioprine-treated inflammatory bowel disease

M.A. Smith; A.M. Marinaki; M. Arenas; M. Shobowale-Bakre; C. M. Lewis; A. Ansari; J. Duley; J.D.  Sanderson

Disclosures

Aliment Pharmacol Ther. 2009;30(4):375-384. 

In This Article

Results

Of the 192 patients included in the analysis, 112 (58%) were women and the mean age was 39 years (16-84). Fourteen (7%) were non-Caucasian. One hundred and five (55%) had Crohn's disease, 86 (45%) ulcerative colitis and a single patient had indeterminate colitis. 77 of 192 (40%) patients withdrew from 2 mg/kg AZA because of adverse effects. The overall per protocol clinical response rate was 71/115 (62%) in those completing 6 months treatment.

The allele frequencies identified in the study cohort were similar to those from online databases ( Table 1 ). SNPs MOCOS c.509T > C, c.1072A > G and c.359G > A were linked, c.509T > C and c.1072A > G were in absolute linkage disequilibrium (r2 = 1, HapMap data) with the minor allele of each SNP occurring together, r2 = 0.89 between these SNPs and c.359G > A (HapMap data). Two of these SNPs were situated in exon 4 and the third (MOCOS c.1072A > G) was in exon 6. In the analysis of clinical outcome, these SNPs were therefore analysed together. All genotypes were in Hardy–Weinberg equilibrium. SNP genotyping was successful in greater than 99% of individuals for all SNPs.

XDH
and MOCOS

Details of genotyping results are shown in Table 2 . Using a dominant model, a weak but significant protection from ADRs was found for the XDH 837T variant (P = 0.048, OR 0.23, 95% CI 0.05–1.05). Interestingly, those individuals carrying the XDH 837T variant had an under-representation of atypical side effects (headache, myalgia, rash, flu-like symptoms, etc.), but this failed to reach statistical significance (P = 0.07), perhaps because of the small number of patients with the XDH 837T variant. A trend towards protection from ADRs was seen with MOCOS 2107C variant, although this did not reach significance (P = 0.058 in a recessive model, P = 0.13 in a dominant model, OR 0.64, 95%CI 0.36–1.15). Interestingly, no patients with a variant MOCOS c.2107A > C and XDH c.837C > T haplotype (n = 7) experienced ADRs (P = 0.019 Chi-square for trend). Analysis of these SNPs, when non-Caucasians had been excluded, had a minor impact on these associations (XDH 837T variant and ADRs P = 0.08, OR 0.26, 95%CI 0.06–1.22, MOCOS 2107C variant and ADRs P = 0.056 in recessive model, OR 0.26, 95%CI 0.36–1.20).

Further investigation into the association with ADRs with MOCOS and XDH was carried out using haplotypes across all markers genotyped in these genes, but no increase in signal was detected (P-values of 0.23 and 0.24 respectively).

There was no relationship observed between any of the XDH or MOCOS SNPs tested and AZA treatment success.

AOX1

A significant association was detected between an AOX1 3404G variant and a lack of clinical response to AZA (P = 0.035, OR 2.54, 95%CI 1.06–6.13). The significance was not altered by excluding non-Caucasians from the analysis (P = 0.036).

Failure to respond to therapy could not be attributed to differences in TGN level, which did not differ significantly between those with and those without the SNP (P = 0.46). Likewise, TPMT was not significantly different between those with and those without the AOX1 SNP (P = 0.44). Excluding from the analysis those patients whose failure to respond was likely to be because of non-adherence to treatment (average TGN < 100 pmol/8 × 108 RBC over the 6 month period) strengthened the association (P = 0.012, OR 6.94, 95%CI 1.58–30.43).

As patients with very high TPMT activity are already known to be at increased risk of non-response,[15–17,41] we analysed the effect of combining this information with a patient's AOX1 c.3404A > G genotype. In patients with both the AOX1 3404G variant and a TPMT greater than 35 pmol/h/mgHb, only 33% (4/12) responded to treatment compared to 44% (24/55) for those with one of these predictors of nonresponse and an 86% (42/49) for those with neither predictor (P < 0.0001 for trend, Figure 2). The P-value remained unaffected by excluding non-Caucasians.

Figure 2.

The percentage of patients achieving a complete response to azathioprine treatment. Patients are stratified according to the number of pharmacogenetic predictors of adverse outcome which they carry.

No association was found between the AOX1 3404G variant and the occurrence of ADRs.

Sequencing

Sequencing of the AOX1 coding region in ten patients (5 with and 5 without the AOX1 3404G variant) confirmed concordance with the real-time SNP genotyping. No additional coding mutations were detected.

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