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 regulator of several genes including the cytochrome P4501 (CYP1) family as well 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 genetic variation has been detected in the human AHR gene. In studies on human AHR, Kawajiri et al. (Pharmacogenetics 1995; 5:151-158) reported a variation at codon 554 that results in an amino acid change from arginine to lysine; the frequency of the variant allele in a Japanese population (n = 277) was 0.43. We investigated the Lys554 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-Africans (n = 55); 0.32 in Canadian Chinese (n = 41); 0.14 in North American Indians (n = 47); 0.12 in French Canadian Caucasians (n = 20); 0.11 in a mixed ethnicity North American group (n = 45); 0.09 in Canadian Inuits (n = 22); and 0.07 in German Caucasians (n = 78). We expressed the human Lys554 allele in an in-vitro transcription-translation system and found that the receptor bearing the R554L substitution had an equivalent ability to that of the wild-type receptor to bind to a dioxin-responsive element following treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The Lys554 allele also was equivalent to the wild-type receptor at stimulating CYP1A1 mRNA expression when transfected into TCDD-treated receptor-deficient mouse Hepa-1 cells. 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 adverse effects of environmental chemicals.
Wong
J M
JM
Department of Pharmacology, University of Toronto, Ontario, Canada.
Harper
P A
PA
Meyer
U A
UA
Bock
K W
KW
Morike
K
K
Lagueux
J
J
Ayotte
P
P
Tyndale
R F
RF
Sellers
E M
EM
Manchester
D K
DK
Okey
A B
AB
D000483:Alleles; D001120:Arginine / Q000235:genetics; D003062:Codon / Q000235:genetics*; D004591:Electrophoresis, Polyacrylamide Gel; D005006:Ethnicity / Q000235:genetics*; D005260:Female; D005787:Gene Frequency / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008239:Lysine / Q000235:genetics; D010375:Pedigree; D016133:Polymerase Chain Reaction / Q000379:methods; D018807:Polymorphism, Single-Stranded Conformational; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics* / Q000502:physiology; D014407:Tumor Cells, Cultured
D003062:Codon; D018336:Receptors, Aryl Hydrocarbon; D001120:Arginine; D008239:Lysine