High frequency of CYP1A1*2C allele in Brazilian populations

Abstract The genetic variability of the CYP1A1 1462V polymorphism (CYP1A1*2C) was investigated in four Brazilian populations: three groups of African descent and one group of European descent. The CYP1A1 polymorphism was analyzed by two different procedures, first by the allele-specific polymerase chain reaction (PCR) method and then by the PCR-restricted fragment length polymorphism (PCR-RFLP) method before digestion with BsrDI. The frequency of CYP1A1*2C was 11% in Brazilians of European descent, a frequency that is slightly higher but not statistically different from that observed in European populations. In Brazilians of African ancestry this value was very high (12% to 15%). This allele was not observed in the only two African populations investigated thus far. By themselves, the two factors of interethnic admixture (with populations of European descent and/or Amerindian populations) and genetic drift cannot explain the high values observed here. Our findings suggest that the CYP1A1*2C allele may possibly be present in Africa, but restricted to some ethnic groups not yet investigated. Environmental factors in South America might also have acted as selective factors increasing the CYP1A1*2C gene frequency. Our data also suggest that the CYP1A1*2C allele might possibly have originated in Africa.

KEY WORDS: AFRICAN BRAZILIANS, EUROPEAN BRAZILIANS, POLYMORPHISM

Most human cancers are related to environmental exposure to genotoxic agents. The carcinogen biotransformation system contains two main classes of enzymes: phase I, which mediates oxidative metabolism, and phase II, which conjugates electrophilic substrates with glutathione (review in Indulski and Lutz 2000).

The CYP1A1 gene is a component of the phase I cytochrome P450 superfamily. This family encodes aromatic hydrocarbon hydroxylase, an enzyme playing a role in the metabolism of polycyclic aromatic hydrocarbons (Nebert 1991), which are regarded as important environmental carcinogens (Drum 1998). Several polymorphisms described for this gene have been associated with an elevated risk of cancer in some populations (Park et al. 1997; Ishibe et al. 1998). Among them, a polymorphic site at exon 7, codon 462, alters the protein structure by replacing an isoleucine with a valine (462V; Hayashi et al. 1991). The 462 Val allele has been reported to be associated with a higher risk for certain types of cancer (Cascorbi et al. 1996; Esteller et al. 1997; Garte 1998). However, in other populations no direct evidence supporting an association between this polymorphism and cancer susceptibility was found (Morita et al. 1997; Marchand et al. 1998).

Such contradictory results may be due, at least in part, to ethnic differences in allele distributions (Game 1998; Inoue et al. 2000). The CYP1A1*Val allele is present at higher frequencies in Asians (from 14% to 35%; Zhao et al. 1995; Duzhak et al. 2000) and Amerindians (from 54% to 97%; Munoz et al. 1998; Kvitko et al. 2000) and at lower frequencies in Europeans (from 2.8% to 5.8%; Cascorbi et al. 1996; Esteller et al. 1997). In the only two African populations so far investigated this allele was not detected (Game et al. 1996; Garte 1998; Masimirembwa et al. 1998). The determination of the distribution of this polymorphism in a larger number of populations can help us to understand the effect of this gene in cancer predisposition.

This investigation describes the distribution of the CYP1A1*Val allele (or CYP1A1*2C, according to the recommended nomenclature for the genetic polymorphisms in human P450 genes [http://www.imm.ki.se/CYPalleles]) in four Brazilian populations.

Subjects and Methods

Blood samples were obtained from three populations of African descent and one population of European descent, as follows:

1. The African Brazilians are from:

a. Porto Alegre, the capital of the southernmost Brazilian state (30 deg 5'S; 51 deg 10'W), whose population is about 1,300,000 inhabitants, 15% of African ancestry and 0.09% of Amerindian origin (www.ibge. gov.br). The samples were collected from ambulatory patients seen at two general public hospitals for prenatal or presurgical examinations (mean age, 38 years; 68% males).

b. Rio de Janeiro, the capital of the eastern state of Rio de Janeiro (22 deg 53'S, 43 deg 17'W), whose population is about 5,800,000 inhabitants, 39% of African ancestry and 0.08% of Amerindian origin (www.ibge.gov.br). The samples were obtained from blood donors of the Hemotherapy Service at a public university hospital (mean age, 34 years; 100% males).

c. Salvador, the capital of the Brazilian northeastern state of Bahia (12 deg 55'S; 38 deg 29'W), whose population is about 2,400,000 inhabitants, 79% of African ancestry and 0.16% of Amerindian origin (www.ibge.gov.br). The samples were obtained from newborn children at a public maternity hospital and from blood donors at a public university hospital (mean age, 29 years; 86% males).

The distance between Porto Alegre and Salvador is about 3000 km, and Rio de Janeiro is situated between these cities (about 1500 km from each one).