BACKGROUND & AIMS:
: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.
背景与目标:
:CYP19A1基因产物芳香酶(CYP19A1)是一种58 kDa的蛋白质,属于细胞色素P450超家族的成员,其促进雌激素从雄激素的生物转化。 CYP19A1的单核苷酸多态性(SNPs)影响酶的活性,并与雌激素依赖性疾病,预后,治疗效果和第三代芳香化酶抑制剂(AIs)的毒性有关。根据种族,CYP19A1等位基因的频率分布将有所不同,并且到目前为止,尚无印度人的数据。使用带有TaqMan分析的qRT-PCR,在163名南印度裔健康受试者中确定了CYP19A1基因功能上重要的多态变异体的频率。观察到SNP rs4646(T),rs10046(T),rs700519(T),rs700518(G),rs727479(G),rs4775936(T),rs10459592(G),rs749292(A)的CYP19A1次要等位基因频率,rs6493497(T)和rs7176005(A)分别为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)和35.9(30.7-41.1)。 CYP19A1 SNP之间存在强连锁不平衡,从所有10个SNP中衍生出16个频率> 1%的不同单倍型结构。最常见的是单倍型(H1)GCTATCTGTG,频率约为17.8%。性别特异性评估显示rs749292的等位基因频率存在显着差异(p <0.04),并且除rs727479外,在CYP19A1变体的分布中检测到更大的种族间差异。我们的结果可为进一步认可AI的药物遗传学研究以及随后的分子流行病学研究提供初步见识,这些研究涉及这些变异对南印度人雌激素依赖性疾病的发生和发展的影响。