Pharmacogenomics Centre (PROMISE), Faculty of Pharmacy, Universiti Teknologi MARA, Selangor, Malaysia.
Indian J Med Res. 2012 Aug;136(2):249-59.
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).
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.
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.
尿苷二磷酸葡萄糖醛酸基转移酶 1A1（UGT1A1）的遗传多态性与患者接受伊立替康治疗时的反应差异广泛相关。已知该酶的缺乏与严重毒性的高发生率有关。本研究的目的是调查与酶活性降低和伊立替康毒性增加相关的 UGT1A1 的三种不同变体（UGT1A16、UGT1A127 和 UGT1A1*28）在马来西亚三个主要族群（马来人、华人、印度人）中的流行率。
共筛选了 306 名无亲缘关系的健康志愿者，以确定 UGT1A128、UGT1A16 和 UGT1A127。从每个受试者采集 5ml 血样并提取 DNA。设计并验证了基于 PCR 的方法以检测 UGT1A1、UGT1A127 和 UGT1A128。对随机选择的样本进行直接 DNA 测序以验证结果。
与中国人（4.9%）相比，马来人和印度人 UGT1A128（7TA/7TA）纯合子的频率高两倍，分别为 8%和 8.8%。然而，它们之间 UGT1A16 和 UGT1A127 的分布没有显著差异。UGT1A127 尚未在白种人和非裔美国人中检测到，在马来西亚的马来人（3.33%）和马来西亚华人（2.0%）中发现。
马来西亚人群中 UGT1A128 的频率存在种族间差异。我们的结果表明，由于其等位变体的高流行率可能导致药物不良反应，因此在给患者开具伊立替康之前需要进行 UUGT1A16、UGT1A128 和 UGT1A127 的基因分型。
