title: A common polymorphism in the human aromatase gene alters the risk for polycystic ovary syndrome and modifies aromatase activity in vitro.
abstract: Aromatase is a key enzyme involved in estradiol and estrone biosynthesis. Given that polymorphisms of the CYP19A1 gene encoding aromatase have been correlated with plasma testosterone levels, CYP19A1 may therefore act as a genetic modifier of the hyperandrogenic phenotype of polycystic ovary syndrome (PCOS). However, no functional CYP19A1 polymorphisms that predict the risk of PCOS have been identified. We explored the role of CYP19A1 genetic variation in a large case-control study involving 1078 samples, in which five common genetic polymorphisms were scored. Human embryonic kidney 293 cells were transiently transfected with a vector encoding either the CYP19A1 wild-type (WT) allele or an Arg(264)Cys variant to evaluate aromatase activity. Cells were cultured with androstenedione and estrone levels were measured using a specific ELISA. The Arg(264)Cys variant of CYP19A1 (rs700519) is associated with PCOS (P= 0.004, corrected P = 0.02). In this functional study, when cells were cultured in varying concentrations of androstenedione (100, 400 and 500 nM), transfection with the Arg(264)Cys variant resulted in increased conversion of androstenedione to estrogen when compared with transfection with the WT construct (P< 0.001). Our data suggest that the common missense polymorphism rs710059 is associated with susceptibility to PCOS and that the Arg(264)Cys variant may increase aromatase enzymatic activity. Overall, these findings imply that aromatase plays an important role in PCOS.
authors.affiliation: Shaanxi Maternal and Child Care Service Center, Xi'an, People's Republic of China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Qiaoli
authors.initials: Q
authors.lastname: Li
authors.forename: Teng
authors.initials: T
authors.lastname: Wang
authors.forename: Guizhong
authors.initials: G
authors.lastname: Yang
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhang
authors.forename: Qing
authors.initials: Q
authors.lastname: Sang
authors.forename: Huan
authors.initials: H
authors.lastname: Wang
authors.forename: Xinzhi
authors.initials: X
authors.lastname: Zhao
authors.forename: Qinghe
authors.initials: Q
authors.lastname: Xing
authors.forename: Juanzi
authors.initials: J
authors.lastname: Shi
authors.forename: Lin
authors.initials: L
authors.lastname: He
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
mesh_terms: D000328:Adult; D000735:Androstenedione / Q000378:metabolism / Q000494:pharmacology*; D001120:Arginine / Q000235:genetics / Q000378:metabolism; D001141:Aromatase / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D002681:China; D003545:Cysteine / Q000235:genetics / Q000378:metabolism; D016172:DNA Fingerprinting; D004967:Estrogens / Q000096:biosynthesis*; D004970:Estrone / Q000096:biosynthesis*; D005260:Female; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D009154:Mutation; D010957:Plasmids; D011085:Polycystic Ovary Syndrome / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D011110:Polymorphism, Genetic; D012307:Risk Factors; D014162:Transfection
chemical_list: D004967:Estrogens; D004970:Estrone; D000735:Androstenedione; D001120:Arginine; D001141:Aromatase; D003545:Cysteine