Frequency of pharmacogenomic variants affecting safety and efficacy of immunomodulators and biologics in a South Asian population from Sri Lanka.

BACKGROUND

Immunomodulators are important for management of autoimmune diseases and hematological malignancies. Significant inter-individual variation in drug response/reactions exists due to genetic polymorphisms. We describe frequency of identified genetic polymorphisms among Sri Lankans.

METHODS

Sri Lankan data were obtained from an anonymized database of 670 participants. Data on variants and global distribution of Minor Allele frequency (MAF) of other populations (South Asian, Ashkenazi-Jewish, East-Asian, European-Finnish, European-non-Finnish, Latino-American, African/African-American) were obtained from pharmGKB online database.

RESULTS

SLC19A1 (rs1051266) variant had a MAF (95% CI) of 63.3% (60.7-65.9). Other common variants included FCGR3A (rs396991), MTHFR (rs1801133), ITPA (rs1127354), CYP2C93 (rs1057910) and NUD153 (rs116855232), with MAFs of 35.3% (32.7-37.9), 12.2% (10.4-13.9), 10.9% (9.2-12.6), 9.8% (8.2-11.4), 8.3% (6.8-9.8) respectively. Less commonly present variants included CYP2C92 (rs1799853) (2.5%[1.7-3.4]), TPMT3C (rs1142345) (1.9%[1.1-2.6]), TPMT3B (rs1800460) (0.2%[0-0.5]), CYP3A56 (rs10264272) (0.2%[0-0.4]) and CYP3A418 (rs28371759) (0.1%[0-0.2]). The SLC19A1 (rs1051266), NUD153 (rs116855232), CYP2C93 (rs1057910), FCGR3A (rs396991), and ITPA (rs1127354) showed significantly higher frequencies in Sri Lankans compared to many other populations, exceptions include FCGR3A in Ashkenazi-Jewish and ITPA in East-Asians. Conversely, MTHFR (rs1801133), TPMT3B (rs1800460), and CYP2C92 (rs1799853) were significantly less prevalent among Sri Lankans than in  many other populations. Sri Lankans exhibited lower prevalence of TPMT3C (rs1142345) compared to European-non-Finnish, Latino-Americans, and African/African-Americans; CYP3A418 (rs28371759) compared to East-Asians; and CYP3A56 (rs10264272) compared to African/African-Americans and Latino-Americans.

CONCLUSION

Sri Lankans exhibit higher frequencies in variants reducing methotrexate efficacy (SLC19A1), increasing azathioprine myelotoxicity (NUDT15), and lower frequencies in variants linked to increased azathioprine toxicity (TPMT3B, TPMT3C), reduced tacrolimus efficacy (CYP3A418), and methotrexate toxicity risk (MTHFR). Beneficial variants enhancing rituximab efficacy (FCGR3A) are more prevalent, while those reducing tacrolimus dosage (CYP3A56) are less common. This highlights need for targeted medication strategies to improve treatment outcomes.