A Genetic Variant Increases Susceptibility to Pancreatitis from Thiopurines

Geneticists have identified a variant that increases risk for pancreatitis 4-fold in patients receiving thiopurine drugs.

Pancreatitis occurs in approximately 4% of patients treated with the thiopurines azathioprine or mercaptopurine. Its development is unpredictable and almost always leads to drug withdrawal.

In a study published September 14 in Nature Genetics, researchers describe a group of patients with a genetic polymorphism that greatly increase their risk for pancreatitis during treatment with these drugs.

Graham Heap et al. identified patients with inflammatory bowel disease (IBD) who developed pancreatitis within 3 months of starting these drugs, from 168 sites worldwide. The authors performed a genome-wide association study on 172 cases and 2035 controls with IBD, and found strong evidence for an association within the class II HLA region, with the most significant association at rs2647087.

Heap et al. replicated their findings in an independent set of 78 cases and 472 controls with IBD matched for drug exposure. Fine mapping of the HLA region identified association with the HLA-DQA1*02:01–HLA-DRB1*07:01 haplotype.

The HLA-DQA1 and HLA-DRB1 genes are located on the short (p) arm of chromosome 6 at position 21.3

The HLA-DQA1 and HLA-DRB1 genes are located on the short (p) arm of chromosome 6 at position 21.3

The authors report that patients heterozygous for the rs2647087 polymorphism have a 9% risk of developing pancreatitis after administration of a thiopurine, and patients that are homozygous have a 17% risk.

Thiopurines are some of the most effective and most commonly used drugs to suppress the immune system in patients with IBD or rheumatoid arthritis, and after some organ transplants.

Heap told NewsMedical that the discovery might allow healthcare workers to identify patients at risk for pancreatitis during thiopurine therapy. “We are hoping that this test will be formed into a tool kit of DNA-based tests that also assess other important side effects of these drugs, such as liver damage or white blood cell counts,” Heap said.

Heap told Pharmacogenomics Reporter that they are investigated whether liver injury or hypersensitivity syndromes are affected by variants at rs2637087.

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