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causes.33

More than 30 different mutations in G6PD are listed in Beutler's review of the molecular biology of G6PD variants. Most of these produce a phenotypically altered enzyme, having abnormal activity, quantity, properties, or a combination of these properties.33

NAT2 Polymorphism

Acetylation polymorphism confers rapid or slow acetylator status on individuals, and is widely acknowledged as a reliable prognosticator of individual susceptibility to effective and safe use of numerous drugs (isoniazid, sulfonamides, procainamide, hydralazine, sulfasalazine, etc.), to toxicity from industrial/ occupational chemicals with carcinogenic potential, and possibly to dietary mutagens. Studies of the global distribution of acetylator gene frequencies encompass measurements on more 10,000 individuals in dozens of different populations since the trait was discovered in the 1950s.34 The percentage of slow acetylators ranges from 80% or more in Egyptians and certain other Middle Eastern populations to 20% or less of Japanese and Canadian Eskimos. Populations of Europeans and African origin have, with few exceptions, intermediate percentages of slow acetylators (Figure 8.2).

The "cline" in slow acetylator frequencies among populations of the Northern hemisphere provides one of the most dramatic illustrations of ethnic variation for any human trait described so far (Figure 8.3). Population surveys of slow acetylator allelic frequencies conducted by Sunahara et al.35 initially disclosed a trend of increasing slow acetylator allelic frequencies from northern to southern latitudes among Japanese. Estimates of ethnic variation in acetylator allelic frequencies based on global observations by Karim et al.36 fully bear out Sunahara's idea of a relationship between latitude and acetylator status and extend them to a number of other populations of the Northern hemisphere. The occurrence of such a trend in the frequency of hereditary traits is a perplexing phenomenon in population and evolutionary genetics. Such phenomena are well known in wild plant and animal populations37 but such relationships are much less numerous between human gene frequencies and the environment.38 We do not know the natural or endogenous substrate for N-acetyltransferase (later shown to be NAT2), so we do not understand the origin of this relationship. Lacking this information, speculation suggests that rapid acetylation may have conferred a selective advantage to

Central & West African

East Asian

Central & West African

East Asian

European

Eskimo

Figure 8.2 Racial differences among the slow acetylator (NAT2) phenotype in various ethnic populations.

European

Eskimo

Figure 8.2 Racial differences among the slow acetylator (NAT2) phenotype in various ethnic populations.

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