Ethnic variability in the allelic distribution of human aryl hydrocarbon receptor codon 554 and assessment of variant receptor function in vitro

The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcriptional r egulator of several genes including the cytochrome P4501 (CYP1) family as w ell as genes encoding factors involved in cell growth and differentiation. In mice, several polymorphic forms of the AHR are known, some of which have altered affinity for toxic and carcinogenic ligands, Remarkably little gen etic variation has been detected in the human AHR gene. In studies on human AHR, Kawajiri et al. (Pharmacogenetics 1995; 5:151-158) reported a variati on at codon 554 that results in an amino acid change from arginine to lysin e; the frequency of the variant allele in a Japanese population (n = 277) w as 0.43. We investigated the Lys(554) allele in 386 individuals of various ethnic origins and found the frequency to be: 0.58 in Ivory Coast Africans (n = 58); 0.53 in a mixed African group (n = 20); 0.39 in Caribbean-African s (n = 55); 0.32 in Canadian Chinese (n = 41); 0.14 in North American India ns (n = 47); 0.12 in French Canadian Caucasians (n = 20); 0.11 in a mixed e thnicity North American group (n = 45); 0.09 in Canadian Inuits (n = 22); a nd 0.07 in German Caucasians (n = 78). We expressed the human Lys(554) alle le in an in-vitro transcription-translation system and found that the recep tor bearing the R554L substitution had an equivalent ability to that of the wild-type receptor to bind to a dioxin-responsive element following treatm ent with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The Lys(554) allele al so was equivalent to the wild-type receptor at stimulating CYP1A1 mRNA expr ession when transfected into TCDD-treated receptor-deficient mouse Hepa-l c ells, It is not yet known if any of the wide variations in allele frequency at codon 554 are related to ethnic differences in susceptibility to advers e effects of environmental chemicals. Pharmacogenetics 11:85-94 (C) 2001 Li ppincott Williams & Wilkins.