Haplotype structures and functional polymorphic variants of the drug target enzyme aromatase (CYP19A1) in South Indian population

CYP19A1 gene product aromatase (CYP19A1) is a 58-kDa protein and belongs to the member of the cytochrome P450 superfamily, which facilitates the bioconversion of estrogens from androgens. Single-nucleotide polymorphisms (SNPs) of CYP19A1 affect the activity of the enzyme and have been implicated in the association of estrogen-dependent disease, prognosis, therapeutic efficacy, and toxicity of third-generation aromatase inhibitors (AIs). Based on ethnicity, the frequency distribution of CYP19A1 alleles will differ, and until now, no data are available for Indians. Using qRT-PCR with TaqMan assays, the frequencies of functionally important polymorphic variants of CYP19A1 gene were determined in 163 healthy subjects of South Indian origin. The observed frequencies of the CYP19A1 minor alleles for the SNPs rs4646 (T), rs10046 (T), rs700519 (T), rs700518 (G), rs727479 (G), rs4775936 (T), rs10459592 (G), rs749292 (A), rs6493497 (T), and rs7176005 (A) are 41.1 (35.8–46.4), 20.0 (15.6–24.3), 33.7 (28.6–38.9), 17.8 (13.6–21.9), 25.8 (21.0–30.5), 19.9 (15.6–24.3), 33.7 (28.6–38.9), 24.9 (20.2–29.5), 35.9 (30.7–41.1), and 35.9 (30.7–41.1), respectively. Strong linkage disequilibrium existed between CYP19A1 SNPs, and sixteen different haplotype structures with a frequency >1 % were derived from all the 10 SNPs tested. The most common being the haplotype (H1) GCTATCTGTG with a frequency of about 17.8 %. Gender-specific assessment showed significant difference in the allele frequency for rs749292 (p < 0.04), and greater inter-ethnic variation was detected in the distribution of CYP19A1 variants except for rs727479. Our results could provide preliminary insight for further pharmacogenetic investigations of AIs as well as for subsequent molecular epidemiological studies on the contribution of these variants to the occurrence and development of estrogen-dependent disease in South Indians.