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GWAS Uncovers Genotype Predictive of Serious Immunosuppressant-caused Pancreatitis

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Originally published Sept. 16.

NEW YORK (GenomeWeb) — A study led by researchers at the University of Exeter Medical School has identified an alteration in the HLA area of the genome that confers up to a 17 percent risk of developing potentially life-threatening pancreatitis in patients with irritable bowel diseases as a side effect of treatment with thiopurine immunosuppressant drugs.

The genome-wide association study — published as a letter in Nature this week — calculated that IBD patients heterozygous for the identified SNP have about a 9 percent risk of developing pancreatitis after treatment with a thiopurine, or about twice the risk for those without the allele. Patients homozygous for the marker are about five times as likely as those with normal genotypes to suffer pancreatitis, with about a 17 percent risk.

Though the marker, rs2647087, is not necessarily predictive enough to offer clear implications for clinical decision making on its own, the researchers believe it could help guide care in the future as part of a panel of markers that describe multiple avenues of risk for serious side effects to this class of drugs.

Thiopurines also cause other adverse reactions. PGx testing of another marker, TPMT, is already used commonly to predict bone marrow suppression caused by these immunosuppressants, but no markers have yet been established to predict increased risk of pancreatitis, liver damage, or hypersensitivity reactions to the drugs.

Graham Heap, the new study's first author, told PGx Reporter this week that the Exeter group is now working to discover other novel markers for side effects like liver injury or hypersensitivity syndromes, which combined with rs2637087 might be a more informative tool for clinicians.

In their pancreatitis study, Heap and his colleagues recruited 433 patients with IBD who developed the side effect from more than 150 international hospitals, then narrowed that cohort down to 248 with confirmed or highly probable thiopurine-induced pancreatitis.

The researchers conducted both an initial discovery study, and then replicated it in an independent set of patients. For the initial GWAS, the researchers genotyped 172 recruited pancreatitis cases and compared them to 2,035 previously genotyped controls — IBD patients matched by disease to the case cohort but not selected at all for treatment with thiopurines or pancreatitis.

Based on the results, the team identified rs1647047, a location within the class II HLA region with a significant association with pancreatitis. The group also found that the HLA alleles HLADQ-A1*0201 and HLA-DRB1*0701 were significantly associated with pancreatitis, and were partially tagged by rs2647087.

The association of rs2647087 remained significant even after the researchers included smoking status, a known risk factor for pancreatitis, in their analysis.

Next, the team set out to replicate the findings in an independent set of 78 cases and 472 controls, this time more stringently designing the control cohort to include only IBD patients treated with thiopurines for at least 12 months without developing pancreatitis. This also revealed a strong association between pancreatitis and rs2647087, as well as several other SNPs in linkage disequilibrium with rs2647087.

Overall, the results indicated that patients heterozygous at the location have about 2.5 times the risk, and those homozygous have approximately five times the risk of those with normal alleles.

According to the authors, this means that in a clinical setting, patients testing homozygous for the SNP would have an approximate 17 percent risk, and those who are heterozygous, a 9 percent risk of developing pancreatitis if prescribed a thiopurine immunosuppressant.

Heap said that the results are the first to uncover a genetic association with drug-induced pancreatitis. While the study was focused on IBD, the group is interested in looking at other diseases like rheumatoid arthritis in which thiopurines are also prescribed, he said.

Because of the design of the study, he said that the researchers are fairly confident that the association they found is not IBD-specific and should hold true for other diseases as well.

The group is also planning to recruit more patients to expand its IBD GWAS. "Although we saw this large effect in HLA there is a possibility of other smaller effects that we weren't powered to see," Heap said.

For rs2647087, Heap added, the effect size the team saw was not as large as some other PGx markers in the HLA region that have yielded more dramatic clinical impact, such as the association between the HLA-B*5701 allele and adverse reactions to the HIV drug Abacavir.

"The odds ratio [for our marker] was about 2.6, which means homozygotes have about a 20 percent risk of getting pancreatitis with this drug," Heap explained. "That's at a level where clinicians would be undecided about whether to give the drug or not because there's an 80 percent chance the patient will be fine."

In the study the researchers attempted to restrict their analyses only to patients who were deemed a definite, not just a probable case of thiopurine-induced pancreatitis. This bumped the odds ratio up to 3.18, but because of the much smaller sample size, only 37 cases, the association did not achieve genome-wide significance, the group wrote.

However, Heap said that the researchers believe that if they can combine rs2647087 in a panel with other predictive markers for other thiopurine side effects, it could have a more definitive clinical impact.

"With a larger panel, if you can predict a 20 percent chance of pancreatitis, and the same patient also has a 20 percent chance of liver injury, for example, then maybe it's clearer that you shouldn't prescribe the drug," he said.

The group now aims to identify additional risk markers and develop such a panel.

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