The 5α-reductase enzyme converts testosterone to dihydrotestosterone, the most potent androgen in certain tissues such as the hair follicle. Increased activity of this enzyme has been seen in the ovaries of patients with polycystic ovary syndrome (PCOS), the most common endocrinopathy in reproductive-aged women. Increased activity of this enzyme may have important clinical implications in PCOS. For example, 5α-reduced androstenedione inhibits aromatase in the ovaries, reducing estrogen production, a possible cause of follicular arrest and thus polycystic ovaries. Our hypothesis is that genetic variation in the gene for 5α-reductase type 1 (SRD5A1) influences the development of PCOS and the severity of hirsutism. We studied 287 white women with PCOS and 187 controls. PCOS was diagnosed using the 1990 NIH criteria. Hirsutism was quantified using the Ferriman-Gallwey (FG) score, with a score of 6 or greater indicating presence of hirsutism. Seven single nucleotide polymorphisms (SNPs) in SRD5A1 were chosen from the International HapMap project such that they would allow efficient identification of the common SRD5A1 haplotypes (a haplotype is a collection of alleles inherited together on the same chromosome). Genotyping was performed using the 5′-exonuclease reaction. Haplotypes and haplotype blocks were constructed using the program Haploview. Association of haplotypes with PCOS risk and presence of hirsutism was assessed using logistic regression and association with FG score using ANCOVA. SNP rs3797179 (C/C versus C/T+TT) was associated with reduced risk of PCOS (OR 0.4, p = .005). We discovered two haplotype blocks in the SRD5A1 gene, block 1 comprising the first five SNPs, block 2 the last two SNPs. Haplotype T-A (block 2) was associated with a 2.5-fold increased risk of PCOS (p = .004), increased risk of hirsutism (OR 2.6, p = .015), and increased FG score (9.3 vs.8.0, p = .013). Haplotype G-G (block 2) was associated with decreased severity of hirsutism with lower FG score (7.8 vs 9.6, p = .018). Haplotype C-G-G-T-T (block 1) was associated with the presence of hirsutism (OR 2.9, p = .009). In conclusion, variation in the SRD5A1 gene not only influences the risk of developing PCOS but also affects the severity of hirsutism in affected women. This is the first report to examine SRD5A1 as a candidate gene in PCOS. Identification of such underlying genes will lead to an increased understanding of the pathophysiology of this common condition, ultimately contributing to advances in risk prediction, disease prevention, and treatment.
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