Ethnic differences polymorphisms

With respect to other ethnic groups, African Americans may have a differential sensitivity to weight gain on clozapine (de Leon etal, 2007). They may also require lower doses than Caucasians (Kelly et al, 2006) and inter-individual as well as ethnic responsiveness maybe partly explained by differences in dopamine receptor polymorphisms (Hwang et al, 2005). It is conceivable that side effects may also be differentially expressed based on pharmacodynamic differences resulting from polymorphisms in other receptor types (histaminergic, muscarinic, etc.). This area remains largely unexplored with respect to ethnic differences in antipsychotic side effects. 

Ethnic differences have been shown to influence response to psychotropic medications. Much of the focus on the explanation for such differences has been on drug-metabolizing (CYP) enzymes of the liver and their sway over pharmacokinetic factors. It is now well recognized that differences in the distribution of polymorphic variants of CYP enzymes exist between different ethnic groups. However, within ethnic groups there are considerable inter-individual variations in drug kinetics, which may not be accounted for solely by genetic variation. Responses to pharmacotherapy are multifaceted and involve the interaction of environmental and... 

Recently, the presence of single nucleotide polymorphisms (SNPs) has been reported for several types of transporter. Extensive studies have been performed on the SNPs of OATP2 [100, 101], and the SNPs identified in African- and European-Americans are indicated in Fig. 12.3. Moreover, the frequency of SNPs differed among the African-American, European-Americans and Japanese, indicating the presence of an ethnic difference in the allelic mutation of this transporter [100, 101]. In addition, some of the mutations were associated with reduced transporter function and/or abnormalities in membrane targeting [100, 102] (Fig. 12.3). It is... 

Tab. 24.2 Inter-ethnic differences in the genotype and allele frequencies (%) of the MDR7 exon 26 C3435T polymorphism. The relevant reference is shown in parentheses...

A variety of ethnic differences have been described in CYP2D6 function. The metabolic ratio - debrisoquine/4-hydroxydebrisoquine ratio in the urine - for a Chinese population was substantially higher than that in a Swedish comparator group - on average the Chinese are poorer metabolizers of debrisoquine than the Swedes - and there is no clear separation between normal and poor metabolizers, i.e., there do not appear to be two separate populations based on genetic polymorphism. 

Asian samples, possible hampering the detection of a positive association of this genotype with response. It is also possible that different polymorphisms in the SERT gene are relevant for response in different ethnic groups. Further studies addressing this issue are certainly warranted. 

B.N. La Du, S. Adkins, Analysis of Serum Para-oxonase/Arylesterase Polymorphism in Some Sudanese Families , in Ethnic Differences in Reactions to Drugs and Xenobiotics, eds. W. Kalow, H.W. Goedde, D.P. Agarwal, Alan R. Liss, New York, 87-98,1986. 

Several factors are likely contributors to the inconsistent findings related to the -75G—>A polymorphism and CAD risk. Among these factors are gender and ethnicity differences, sample size bias when small sample sizes are used, presence of this polymorphism in different haplotypes, and environmental interactions. In regard to gene-environment interactions, Sigurdsson et al. reported that the -75A allele was only associated with increased HDL-cholesterol or apo A-I concentrations in nonsmoking men.26... 

Another widely studied apo A-IV SNP is an A—>T polymorphism at nucleotide 2346 (first base of codon 347), which causes a threonine-to-serine substitution in the protein product.54-55 The A—>T variant at codon 347 occurs at almost double the frequency of the 360G—>T variant with a prevalence of 22% in Caucasian populations.55-56 However, ethnic differences have been described with lower frequencies in African blacks (9.5%) and Hispanic populations (12.9%).53 The 360G— T and 347A—>T genetic variants are in strong linkage disequilibrium and tend not to occur together.55-57... 

Sasso EH, Buckner JH, Suzuki LA. Ethnic differences of polymorphism of an immunoglobulin VH3 gene. J Clin Invest 1995 96(3) 1591 600. 

CYP2D6 was perhaps the first and best characterized of the polymorphic P450 enzymes. The PM phenotype is characterized clinically by a marked deficiency in the metabolism of certain compounds, which can result in drug toxicity or reduced efficacy. The prevalence of the PM phenotype shows marked ethnic differences, with a mean value of approximately 7% in Caucasian populations (97) but 1 % or less in Orientals (98). There are many different CYP2D6 alleles identified, including some that result in an ultrarapid metaboliser phenotype (99), and the typically applied genotyping methodologies are 90% predictive of phenotype (100). 

Miners et al. reported an ethnic difference in the His268Tyr (802 C>T) variant (99). In 91 Caucasians, the allele frequency for UGT2B7 2 (802 C>T) was 0.482 versus 0.268 for 84 Japanese subjects. Patel et al. reported a potential polymorphism in the ratio of (R)- and (iS )-oxazepam glucuronides in urine (100). While (J )-oxazepam is a substrate for UGT2B7, the turnover is very low and there was no difference between the UGT2B7 variants in terms of stereoselectivity (99). More recent data indicates that (.Sj-oxazepam is a UGT2B17 substrate. 

M. S., Cytochrome P450 3A genetic polymorphisms and inter-ethnic differences. Methods Find. Exp. Clin. Pharmacol. 27,559-567,2005 Sarlis,... 

Ozawa S, Soyama A, Saeki M, Fukushima-Uesaka H, Itoda M, Koyano S, Sai K, Ohno Y, Saito Y, Sawada J. Ethnic differences in genetic polymorphisms of CYP2D6, CYP2C19, CYP3AS and MDRl/ABCBl. Drug Metab Pharmacokmet 2004 19(2) 83-95. 

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