Asian phenotypes

Based on the population genotype-phenotype studies performed to date, assays for the molecular diagnosis of TPMT deficiency have focussed on alleles TPMT 2, TPMT 3A and TPMT 3C, as these represent 80-95% of all mutant alleles of this gene in Caucasians [46, 50]. However, the frequency and pattern of mutant alleles of this gene is different among various ethnic populations. For example, Southwest Asians (Indian, Pakistani) have a lower frequency of mutant TPMT alleles and all mutant alleles identified to date are TPMT 3A (Table 24.1) [52]. This is in contrast to Kenyans and Ghanaians where the frequency of mutant alleles is similar to Caucasians, and all mutant alleles are TPMT 3C (Table 24.1) [53, 54]. Among African Americans, TPMT 3C is the most prevalent allele, but TPMT 2... 

Frequency 45-65% of Caucasians and African Americans 10-15% of Asians Slow inactivation of drugs such as isoniazid (for tuberculosis), dapsone (for leprosy), and hydralazine (for high blood pressure), leading to toxicity from the drug at doses well tolerated in people with rapid acetylator phenotype Clinical consequences depend on the specific side effects of the drugs... 

Susceptibility to bladder cancer in humans has been linked to the slow acetylator phenotype of the polymorphic NAT2 AT-acetyltrans-ferase gene. In a study from China, a 25-fold increase in bladder cancer incidence and a 17-fold increase in bladder cancer mortality were determined in 1972 benzidine-exposed workers. In the Asian population the slow acetylator phenotype occurs significantly less often than in Caucasian populations, but an association between those who contracted bladder cancer and phenotype has yet to be determined for this group. Other, more recent data have suggested that the acetylation rate may not be an important risk factor for developing bladder cancer. ... 

Marinaki AM, Arenas M, Khan ZH et al. Genetic determinants of the thiopurine methyltransferase intermediate activity phenotype in British Asians and Caucasians. Pharmacogenetics 2003 13 ... 

Recent haplotype-phenotype studies have also indicated that the genetic relevance to toxic events varies depending on ethnicity and regimen. On this point, it must be noted that lAl 6 in East-Asians is also an important risk factor for severe neutropenia. In contrast, the effects of UGTIA genotypes on the anti-tumor responses to irinotecan treatment remain imclear. Therefore, further clinical studies are needed to evaluate the benefits of the genotyping of 28 and 6 or other markers in terms of irinotecan efficacy. 

Balram C, Sharma A, Sivathasan C, Lee EJD. Frequency of C3435T single nucleotide MDR1 genetic polymorphism in an Asian population phenotypic-genotypic correlates. Br J Clin Pharmacol 2003 56 78-83. 

Second, there are often different variants in different populations some phenotypic consequences of CYP2D6 variations are shown as an example in Figure 2 (1). There is a lower average enzyme activity in both, Chinese and Africans, in comparison to that in Europeans. These differences in activity represent structural changes of the CYP2D6 protein that affect enzyme function. However, the enzyme structures that cause the lower activities are different in the Chinese (13) and in the African populations (14). It is an independent fact that enzyme absence is more rare in Asians and Africans than in Europeans (4). 

Mephenytoin has been extensively used for phenotyping purposes however, such use is not without practical problems. For example, sedation is often observed in PMs, especially those of small body size, e.g., children and Southeast Asians, following administration of a 100-mg dose usually used for phenotyping (178). Accordingly, a dose of 50-mg mephenytoin is often used to phenotype such individuals. A further complicating factor is that racemic mephenytoin (Mesantoin , Sandoz/Novartis, Basal, Switzerland) is not available in many parts of the world. For these reasons, other in vivo probes have been investigated. 

PMs in such groups by phenotyping is not as clear-cut as in European- and Southeast Asian-derived populations this problem is compounded by the low prevalence of this subgroup in these populations. This would appear to be one situation in which putative classification as a PM requires confirmation by genotyping. 

Sohn DR, Kusaka M, Shin SG, et al. Utility of a one-point (3-hour postdose) plasma metabolic ratio as a phenotyping test using metoprolol in two East Asian populations. Ther Drug Monit 1992 14 184—189. 

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