Abstract
CYP19A1 facilitates the bioconversion of estrogens from androgens. CYP19A1 intron single nucleotide polymorphisms (SNPs) may alter mRNA splicing, resulting in altered CYP19A1 activity, and potentially influencing disease susceptibility. Genetic studies of CYP19A1 SNPs have been well documented in populations of European ancestry; however, studies in populations of African ancestry are limited. In the present study, ten ‘candidate’ intronic SNPs in CYP19A1 from 125 African Americans (AA) and 277 European Americans (EA) were genotyped and their frequencies compared. Allele frequencies were also compared with HapMap and ASW 1000 Genomes populations. We observed significant differences in the minor allele frequencies between AA and EA in six of the ten SNPs including rs10459592 (p<0.0001), rs12908960 (p<0.0001), rs1902584 (p = 0.016), rs2470144 (p<0.0001), rs1961177 (p<0.0001), and rs6493497 (p = 0.003). While there were no significant differences in allele frequencies between EA and CEU in the HapMap population, a 1.2- to 19-fold difference in allele frequency for rs10459592 (p = 0.004), rs12908960 (p = 0.0006), rs1902584 (p<0.0001), rs2470144 (p = 0.0006), rs1961177 (p<0.0001), and rs6493497 (p = 0.0092) was observed between AA and the Yoruba (YRI) population. Linkage disequilibrium (LD) blocks and haplotype clusters that is unique to the EA population but not AA was also observed. In summary, we demonstrate that differences in the allele frequencies of CYP19A1 intron SNPs are not consistent between populations of African and European ancestry. Thus, investigations into whether CYP19A1 intron SNPs contribute to variations in cancer incidence, outcomes and pharmacological response seen in populations of different ancestry may prove beneficial.
Highlights
Cytochrome P450 19A1 (CYP19A1) encodes the enzyme aromatase, which catalyzes the conversion of the C19 androgens, androstenedione and testosterone, to estrone and estradiol, respectively [1,2]
Ten CYP19A1 single nucleotide polymorphisms (SNPs) genotyped in this study were selected based upon their previously published associations with cancer risk and outcomes (Table 1), predicted localization within regulatory binding regions, and/or their predicted association with regulatory proteins involved in pre-mRNA processing, mRNA metabolism and transport, and gene expression (Table 2)
We hypothesized that the allele frequency distributions in CYP19A1, because of its association with breast cancer and role in estrogen biosynthesis, may be different between populations of African and European ancestry from Arkansas
Summary
Cytochrome P450 19A1 (CYP19A1) encodes the enzyme aromatase, which catalyzes the conversion of the C19 androgens, androstenedione and testosterone, to estrone and estradiol, respectively [1,2]. Studies have identified SNPs in CYP19A1 that are associated with cancer risk primarily in European Americans (EA), North Indian and Chinese populations [5,6]. Variations in the allele frequencies of several CYP19A1 SNPs and their haplotype distributions, especially rs10459592, rs749292, and rs6493497, have been documented within South Indian, Korean, Hawaiian, Japanese, Latina and populations of European descent within the United States [7,8,9]. It is likely that ancestral differences in the frequencies of functional CYP19A1 SNPs can influence disease susceptibility and risk prediction. Genetic studies of CYP19A1 SNPs in populations of African ancestry are limited
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