Polymorphisms of UGT1A1(*)6, UGT1A1(*)27 & UGT1A1(*)28 in three major ethnic groups from Malaysia

BACKGROUND & OBJECTIVES: Genetic polymorphisms of uridine diphosphate glucuronyltransferase 1A1 (UGT1A1) have been associated with a wide variation of responses among patients prescribed with irinotecan. Lack of this enzyme is known to be associated with a high incidence of severe toxicity. The objective of this study was to investigate the prevalence of three different variants of UGT1A1 (UGT1A1(*)6, UGT1A1(*)27 and UGT1A1(*)28), which are associated with reduced enzyme activity and increased irinotecan toxicity, in the three main ethnic groups in Malaysia (Malays, Chinese and Indians). METHODS: A total of 306 healthy unrelated volunteers were screened for UGT1A1(*)28, UGT1A1(*)6 and UGT1A1(*)27. Blood samples (5 ml) were obtained from each subject and DNA was extracted. PCR based methods were designed and validated for detection of UGT1A1(*)6, UGT1A1(*)27 and UGT1A1(*)28. Direct DNA sequencing was performed to validate the results of randomly selected samples. RESULTS: Malays and Indian have two-fold higher frequency of homozygous of UGT1A1(*)28 (7TA/7TA) which was 8 and 8.8 per cent, respectively compared to the Chinese (4.9%). However, the distribution of UGT1A1(*)6 and UGT1A1(*)27 showed no significant differences among them. UGT1A1(*)27 which has not been detected in Caucasian and African American population, was found in the Malaysian Malays (3.33%) and Malaysian Chinese (2.0%). INTERPRETATION & CONCLUSIONS: There was interethnic variability in the frequency of UGT1A1(*)28 in the Malaysian population. Our results suggest that genotyping of UGT1A1(*)6, UGT1A1(*)28 and UGT1A1(*)27 need to be performed before patients are prescribed with irinotecan due to their high prevalence of allelic variant which could lead to adverse drug reaction.