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 (UGT1A16, UGT1A127 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 UGT1A128, UGT1A16 and UGT1A127. Blood samples (5 ml) were obtained from each subject and DNA was extracted. PCR based methods were designed and validated for detection of UGT1A1, UUGT1A127 and UUGT1A128. 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 UGT1A128 (7TA/7TA) which was 8 and 8.8 per cent, respectively compared to the Chinese (4.9%). However, the distribution of UGT1A16 and UGT1A127 showed no significant differences among them. UGT1A127 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 UGT1A128 in the Malaysian population. Our results suggest that genotyping of UUGT1A16, UGT1A128 and UGT1A127 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.