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Ingelman-Sundberg proposed that certain dietary components may have exerted selective pressure to explain the preservation of alleles with multiple CYP2D6* copies.51'55 He suggested that the presence of CYP2D6* alleles, which have a very high affinity for various plant-derived alkaloids, could provide a high detoxification potential for individuals exposed to diets containing these substances. In support of this hypothesis he notes that very few CYP2D6* with inactivating mutations are found in Ethiopia and Saudi Arabia.

Polymorphic variants of CYP2C19* also exhibit significant ethnic variation. The CYP2C19* polymorphism, originally identified as the mephenytoin polymorphism, is a recessively (codominantly) inherited trait that is important because it determines the metabolic elimination of at least 15% of prescribed drugs, including antiulcer proton pump inhibitors such as omeprazole and pantoprazole, the antimalarial proguanil, and a number of barbiturate hypnotics. The frequency of CYP2C19* poor metabolizers is 2-5% in Caucasians but is much higher in Oriental populations (13-23%). The data on specific CYP2C19 variants indicate the frequency of poor metabolizers with the ml (CYP2C19*2) variant is high in Japanese compared to Caucasians. Another variant, m2 (CYP2C19*3), occurs in Japanese and Africans but has not been detected in Caucasians. The wt, m1, and m2 variants account for almost 100% of the variation in Chinese and Japanese poor metabolizers, but these and additional allelic variants account for only about 92% of the variation in Caucasians.56

Two other features regarding ethnic variation in CYP2D6 and CYP2C19 are brought out by the study of Evans and colleagues. They determined the frequencies of these polymorphisms in Filipinos in Bombay and Saudi Arabians in Riyadh and compared them with historical frequencies in Asian and Caucasian populations.57 Saudi Arabians and other Middle Easterners resemble Europeans in the frequency of CYP2C19 poor metabolizers, but resemble Asians in the frequency of CYP2D6 poor metabolizers. Because of these findings, Middle Eastern populations should be relatively well protected from adverse drug reactions associated with both these recessive phenotypes. Moreover, the distribution of the frequency of the recessive CYP2C19 allele controlling poor metabolism as measured in 18 populations residing at various longitudes is related to longitude. Thus, there is a longitudinal cline that contains an apparent discontinuity between Riyadh and Bombay.

Potassium Channel Polymorphisms and the Long QT Syndrome

Ackerman and colleagues have shown that there are striking differences in risk of sudden death among various ethnic groups that are predisposed to the long QT syndrome (LQTS).58 The LQTS is recognized as a primary channelopathy caused by mutations in five genes that encode cardiac channel subunits. To determine the spectrum, frequency, and ethnic sensitivity of channel variants genomic DNA from 744 apparently healthy subjects was subjected to comprehensive mutational analysis—305 blacks, 187 whites, 134 Asians, and 118 Hispanics were included. Overall, 49 distinct amino acid-altering variants, 36 new, were identified. Two known common polymorphisms, K897T-HERG and G38S-minK, were identified in all four ethnic groups. Excluding the common polymorphisms, 25% of black subjects had at least one nonsynonymous potassium channel variant compared with 14% of white subjects (p < 0.01).

Interestingly, 86% (42/49) of the variants were ethnic specific, with 26 variants found in blacks only, 12 in whites, 2 in Asians, and 2 in Hispanics only. Every variant identified in white, Asian, and Hispanic subjects was confined to the cytoplasmic N- and C-terminal domains of the channel subunits. Of the 11 KVLQT1 variants found in blacks, four were localized to key structural (trans-membrane-spanning) domains.

This study shows that after excluding the common polymorphisms, approximately one in three black subjects and one in seven white subjects harbor one or more potassium channel variants. Thus, functionally relevant variants in cardiac channels are significantly more frequent in blacks than in other ethnic groups, and are of greater channel diversity in black subjects. Whether individuals harboring such channel variants are at greater risk of lethal arrhythmias is not known but warrants careful scrutiny.

CCR5A32 Polymorphism

The chemokine coreceptor CCR5 is required for attachment and infectivity of HIV-1. A 32-base pair deletion of this receptor gene, CCR5A32, yields a nonfunctional receptor that blocks entry of HIV-1 and slows progression of AIDS in adult patients.59-61 A genotype survey of 38 ethnic populations including 4166 individuals revealed a cline of CCR5A32 allele frequencies of 0-14% across Eurasia but the variant is absent in African, American Indian, and East Indian ethnic groups.62 Its rarity or absence in non-Caucasian populations led to the speculation that the mutation occurred only once in the ancestry of Caucasians, subsequent to the separation of Caucasians from African ancestors estimated to be 150,000-200,000 years ago. Based on haplotype analysis combined with linkage analysis to two microsatellite loci, the origin of the CCR5A32-containing ancestral haplotype was estimated to be ~700 years ago (range 275-1875 years). The geographic cline and its recent emergence suggested a historic event, possibly a widespread fatal epidemic of a pathogen such as HIV-1 or another infectious agent such as Shigella, Salmonella, or Mycobacterium tuberculosis that utilizes CCR5, elevating its frequency in ancestral Caucasian popula tions. An alternative hypothesis suggests that epidemics of bubonic plague or smallpox may provide a better explanation for its prevalence in Caucasian populations.63

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