P0679 - Combination of TPMT and NUDT15 Gene Variants Are Better at Predicting Risk of Azathioprine-Induced Leukopenia Than Either Alone in Middle Eastern Saudi Patients With Inflammatory Bowel Disease

Yasser Meeralam, MD, Adnan AlZanbagi, MD, Mona AlSaedi, MD, Mohammed Khan, MD, Wafi AlMutawa, MBChB, Abdulrahman Bosfar, MBChB, Mohammed Shariff, MD
King Abdullah Medical City, Makkah, Makkah, Saudi Arabia

Introduction: Thiopurine induced myelosuppression is a well-recognized adverse event and is associated with genetic variants in thiopurine methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15) gene. Loss-of-function alleles has been well characterized in different ethnic groups. However, the prevalence of these variants in Middle Eastern patients with inflammatory bowel disease (IBD) has not been reported. Thus this study aims to investigate the prevalence of TPMT and NUDT15 polymorphism in Saudi patients with IBD and its influence on myelosuppression in patients taking azathioprine

Methods: Patients with a confirmed diagnosis of IBD from a tertiary referral center in Makkah who had both TPMT (variants: c.238 G > C, c.460 G > A, and c.719A > G) and NUDT15 (variants: c.36_37insGGAGTC, c.52G > A, c.415C > T, c.416G > A) genotyping done in patients taking azathioprine were retrospectively evaluated for evidence of myelosuppression by checking complete blood count.

Results: TPMT and NUDT15 genotyping was done in 59 patients with IBD having a mean age of 29.2 years (SD 9.81) including 25 females (males = 34) and 45 patients with Crohn’s disease (ulcerative colitis = 14). Two patients (3%) carried the TPMT variant allele and rest the wild type (97%). Fifty-six patients (95%) carried the wild type NUDT15 genotype and three (5%) variant alleles. Eighteen patients (31%) developed thiopurine-induced leucopenia (TIL). Sixteen patients (16/56, 29%) with wild type NUDT15 genotype developed TIL in comparison to two patients with NUDT15 variant (2/3, 67%), thus NUD15 polymorphism was not strongly associated with TIL (odds ratio 7.11; 95% CI 0.28-183.30, p=0.24). Similarly TMPT polymorphism was not associated with TIL although both the patients carrying the TMPT variants developed TIL (odds ratio 12.58; 95% CI 0.58-276.25, p=0.11). However, the combination of both NUD15 and TMPT genotyping was significantly associated with risk of TIL (odds ratio 11.43; 95% CI 1.17-111.10, p=0.03).

Discussion: This is the first study of its kind, in modest number of patients, to report the prevalence of TPMT and NUDT15 haplotypes in Middle Eastern Saudi patients with IBD. The prevalence of NUD15 was slightly higher than TMPT polymorphism. Combined testing for both the genotypes was more helpful in predicting TIL than either alone. Efforts are ongoing to test this in a larger cohort of patients.


Disclosures:


Yasser Meeralam, MD, Adnan AlZanbagi, MD, Mona AlSaedi, MD, Mohammed Khan, MD, Wafi AlMutawa, MBChB, Abdulrahman Bosfar, MBChB, Mohammed Shariff, MD. P0679 - Combination of TPMT and NUDT15 Gene Variants Are Better at Predicting Risk of Azathioprine-Induced Leukopenia Than Either Alone in Middle Eastern Saudi Patients With Inflammatory Bowel Disease, ACG 2023 Annual Scientific Meeting Abstracts. Vancouver, BC, Canada: American College of Gastroenterology.