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Variants in the 5-Reductase Type 1 and Type 2 Genes Are Associated with Polycystic Ovary Syndrome and the Severity of Hirsutism in Affected Women

Division of Endocrinology, Diabetes, and Metabolism, Departments of Medicine (M.O.G., N.A.S., H.J.A.) and Obstetrics and Gynecology (M.O.G., M.P., R.A.,), and Medical Genetics Institute (M.O.G., X.G.), Cedars-Sinai Medical Center, Los Angeles, California 90048; and Departments of Medicine (M.O.G., R.A.) and Obstetrics and Gynecology (R.A.), the David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California 90025

Address all correspondence and requests for reprints to: Ricardo Azziz, M.D., M.P.H., M.B.A., Department of Ob/Gyn and Center for Androgen Related Disorders, Cedars-Sinai Medical Center, 8635 West Third Street, Suite 160W, Los Angeles, California 90048. E-mail: azzizr{at}cshs.org.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Context: Despite the importance of dihydrotestosterone in androgen action, polymorphisms in the genes for the two isoforms of 5-reductase (SRD5A1 and SRD5A2) have not been evaluated as risk factors for polycystic ovary syndrome (PCOS).

Objective: The objective of the study was to test the hypothesis that haplotypes in the SRD5A1 and SRD5A2 genes are risk factors for PCOS and the severity of hirsutism in affected women.

Design: PCOS and control subjects were genotyped for seven single-nucleotide polymorphisms in SRD5A1 and eight single-nucleotide polymorphisms in SRD5A2. Haplotypes were determined and tested for association with PCOS diagnosis and component phenotypes.

Setting: Subjects were recruited from the reproductive endocrinology clinic at the University of Alabama at Birmingham; control subjects were recruited from the general surrounding community. Genotyping took place at Cedars-Sinai Medical Center in Los Angeles.

Participants: A total of 287 White women with PCOS and 187 controls participated.

Main Measurements: SRD5A1 and SRD5A2 genotype, quantitative hirsutism score, and hormonal and metabolic phenotypes were assessed.

Results: Haplotypes within both genes were associated with PCOS risk. The Leu allele of the Val89Leu variant in SRD5A2 was associated with protection against PCOS; this allele is known to modestly reduce 5-reductase activity. Haplotypes in SRD5A1 but not SRD5A2 were also associated with the degree of hirsutism in affected women.

Conclusions: This study presents genetic evidence suggesting an important role of both isoforms of 5-reductase in the pathogenesis of PCOS. That only SRD5A1 haplotypes were associated with hirsutism suggests that only this isoform is important in the hair follicle.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
POLYCYSTIC OVARY SYNDROME (PCOS), the most common endocrinopathy in reproductive-aged women, is characterized by hyperandrogenism, oligoovulation, and polycystic ovaries. Familial aggregation suggests the existence of genes that affect PCOS susceptibility. Affected women display varying degrees of hirsutism (1), in part related to ethnicity (2), suggesting that genes may influence the severity of hirsutism in PCOS. An enzymatic activity that is crucial to androgen action is steroid 5-reductase, which converts testosterone to the more potent androgen dihydrotestosterone (DHT). Ovarian and peripheral 5-reductase activity appears to be increased in PCOS (3, 4, 5, 6, 7, 8). We hypothesize that genetic variation in the genes coding for 5-reductase may be risk factors for PCOS as well as the severity of hirsutism within women with PCOS.

The two isoforms of 5-reductase, type 1 and type 2, are encoded by distinct genes, SRD5A1 and SRD5A2, located on chromosomes 5p15 and 2p23, respectively. Although both catalyze the 5-reduction of testosterone to DHT, the two enzymes differ in their kinetic properties and expression patterns. Transcripts for both enzymes have been detected in the ovary, where 5-reductase activity may contribute to follicular arrest (3) and thus possibly the pathogenesis of PCOS. Variable function of 5-reductase in the hair follicle is also thought to contribute to varied expression of hirsutism in women with PCOS. In this study, we present the first large-scale genetic association study of the SRD5A1 and SRD5A2 genes in PCOS, using haplotypes to capture common variation across genomic regions. We report that haplotypes in both SRD5A1 and SRD5A2 are risk factors for PCOS; however, variants in only SRD5A1 are associated with the severity of hirsutism.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects

A total of 287 consecutive White patients with PCOS, aged 13–47 yr, and 187 healthy White control women, aged 14–60 yr, were recruited from the Birmingham, Alabama, area.

PCOS subjects were recruited consecutively from the reproductive endocrine practice of one of the investigators (R.A.) at the University of Alabama at Birmingham. Participation in research studies was offered to patients meeting inclusion criteria (premenopausal, nonpregnant, on no hormonal therapy for at least 3 months, and meeting diagnostic criteria for PCOS). Presence of PCOS was defined by the 1990 National Institutes of Health consensus criteria (9), including 1) clinical hyperandrogenism and/or hyperandrogenemia, 2) oligoovulation, and 3) the exclusion of related disorders, including androgen-producing tumors, nonclassic 21-hydroxylase-deficient adrenal hyperplasia, hyperprolactinemia, active thyroid disease, or Cushing’s syndrome. The specific parameters for defining hirsutism, hyperandrogenemia, ovulatory dysfunction, and exclusion of related disorders were previously reported (10).

Controls were healthy women with regular menstrual cycles or a history of regular menstrual cycles before menopause and without family history of hirsutism. These women had no evidence of hirsutism, acne, alopecia, or endocrine dysfunction. Controls were recruited by word of mouth and advertisements in the Birmingham, Alabama, area through a call for healthy women without detailing further the nature of the studies. All controls underwent a brief history and physical exam (see below) to ensure that all control women included were nonhirsute and eumenorrheic.

No subject (PCOS or control) had used hormonal preparations, including oral contraceptives, for at least 3 months preceding the study, and none were pregnant. All subjects also gave written informed consent, and the study was performed according to the guidelines of the Institutional Review Boards of University of Alabama at Birmingham and Cedars-Sinai Medical Center.

Phenotyping

Subjects underwent a brief physical examination, hirsutism scoring using a modification of the Ferriman-Gallwey method (mFG) (11), and blood sampling. Subjects were deemed hirsute if their mFG score was 6 or greater (11); all hirsutism scoring was performed by the same investigator (R.A.). Hormonal measures, including total and free testosterone, dehydroepiandrosterone sulfate (DHEAS), 17-hydroxyprogesterone, and SHBG, were obtained between d 3 and 8 (follicular phase) after a spontaneous menstrual cycle or progesterone-induced withdrawal bleed, as described (10). The same laboratory assays were employed for all subjects. For these hirsutism and androgen-related traits measured in the women with PCOS, completeness of data was over 98%. The total and free testosterone values of three cases were clear outliers and were deleted from analysis.

Fasting glucose and insulin were also obtained in a subset of the cohort (70%). The computer-based homeostasis model assessment (HOMA) (www.dtu.ox.ac.uk/homa) uses fasting glucose and insulin to calculate indices of insulin resistance (HOMA-IR) and insulin secretion (HOMA-%B) (12, 13). An ideal, normal-weight person less than 35 yr of age has a HOMA-IR of 1 and HOMA-%B of 100% (14).

Genotyping and haplotype determination

We selected seven single-nucleotide polymorphisms (SNPs) (rs472402, rs2677933, rs248805, rs3822430, rs10060745, rs3797179, and rs39848) that span the 36.1-kb genomic length of SRD5A1, including four [rs248805, rs3822430 (Pro103Pro), rs3797179, and rs39848] predicted to tag the haplotypes (across the entire gene) occurring at more than 1% frequency in the Caucasian population of the HapMap database (15). Eight SNPs [rs11889731, rs7571644, rs12470143, rs12467911, rs2300697, rs11675297, rs2754530, and rs523349 (Val89Leu)] across the 56.4-kb SRD5A2 gene were genotyped, including six (rs11889731, rs7571644, rs12470143, rs2300697, rs11675297, and rs2754530) predicted to tag the common haplotypes across the entire gene in the Caucasian population of the HapMap database. The 15 SNPs were genotyped in the 474 subjects using the 5'-exonuclease assay (TaqMan MGB; Applied Biosystems, Foster City, CA) described previously (16, 17). The PCR primers and TaqMan MGB probes are presented in Table 1.

Statistical analysis

For all analyses, quantitative trait values were log or square root transformed as appropriate to reduce nonnormality. Unpaired t tests and ² tests were used to compare clinical characteristics between women with and without PCOS.

The primary phenotypes for genetic association analysis were the presence or absence of PCOS, presence or absence of hirsutism, and the mFG score (the latter two traits within PCOS only). To confirm the significant haplotypic associations with the primary traits, we estimated empirical P values by permutation analysis. For each haplotype block, the samples were permuted by shuffling haplotypic data 1000 times, and subsequent association analyses were carried out to obtain the distribution of the test statistic under the null hypothesis of no association. The empiric P values were obtained as the proportion of the 1000 replicates that had a P value less than or equal to the nominal ones obtained from the actual (unshuffled) data. These empiric P values are reported in Results.

Secondary analyses included the androgen-related traits (total and free testosterone, DHEAS, 17-hydroxyprogesterone, and SHBG) and insulin-related traits (fasting insulin, fasting glucose, HOMA-IR, and HOMA-%B) within the PCOS cohort. Secondary traits were analyzed for association only with haplotypes that showed association with primary traits. The secondary analyses were subjected to Bonferroni correction given their exploratory nature. For the insulin-related traits only, subjects with diabetes (n = 6) were excluded because the hyperglycemia of diabetes may induce secondary changes in insulin-related traits that reduce their utility for genetic analyses.

Haplotypes were the genotypic unit used in association analyses. Haplotypes were assigned before association analyses. Association of haplotypes with PCOS and presence/absence of hirsutism was evaluated using logistic regression. Association with mFG score, androgens, and insulin-related traits was evaluated using analysis of covariance. All analyses (logistic regression and analysis of covariance) were adjusted for age and body mass index (BMI) by including them as independent variables in each analysis. The ² test was used to compare haplotype frequencies and allele frequencies of the Val89Leu polymorphism in SRD5A2 between PCOS and controls. Significance was taken as P < 0.05. Analyses were carried out using Statview 5.0 (SAS Institute, Cary, NC).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The clinical characteristics of the 287 women with PCOS and 187 controls are presented in Table 2. Subjects with PCOS were younger, more obese, more hyperandrogenemic, more hirsute, and more insulin resistant and had higher ß-cell function (insulin secretion) and lower SHBG levels than control subjects.

We genotyped seven SNPs spanning the SRD5A1 gene (Fig. 1). All markers were in Hardy-Weinberg equilibrium. Linkage disequilibrium (D') among the seven SNPs in our subjects ranged from 0.12–1.0, with an average D' of 0.80. The patterns of linkage disequilibrium among the SNPs determined two haplotype blocks within the gene, the first block (block 1 in Fig. 1) comprised of the first five SNPs at the 5' end of the gene; the second block (block 2 in Fig. 1) comprised of the remaining two SNPs at the 3' end of the gene. Linkage disequilibrium within block 1 was high, with an average D' of 0.99 (range, 0.94–1). Linkage disequilibrium between the two SNPs comprising the second block was 1. Table 3 displays the SRD5A1 haplotypes and their frequencies.

View larger version (57K): [in this window] [in a new window]   FIG. 1. Gene structure and linkage disequilibrium plot for SRD5A1. The gene structure of SRD5A1 is shown at the top; the gene has five exons. The locations of the genotyped SNPs relative to the exons are indicated. The linkage disequilibrium plot at the bottom displays D' values (percent) for each pair of SNPs in the box at the intersection of the diagonals from each SNP. The dark solid blocks indicate D' = 1 (100%) for the corresponding pair of variants. The two haplotype blocks are indicated.

Several other haplotypes in SRD5A1 were also associated with measures of hirsutism in subjects with PCOS. The second most common haplotype in block 2, CG, was associated with decreased mFG score (carriers mean score 7.8 ± 4.5, noncarriers 9.6 ± 5.5, P = 0.011). In block 1, the third most common haplotype, CGGTT, was associated with both increased presence of hirsutism (odds ratio 2.93, 95% confidence interval 1.31–6.5, P = 0.041) and increased mFG score (carriers 9.0 ± 3.9, noncarriers 8.0 ± 5.1, P = 0.038). The second most common haplotype in block 1, CAGCC, was associated with a trend to decreased mFG score (carriers 7.8 ± 4.9, noncarriers 8.9 ± 4.7, P = 0.085).

Given the association of the above haplotypes with PCOS and hirsutism-related traits, secondary analyses were carried out to evaluate whether these same haplotypes were associated with androgen- or insulin-related quantitative traits. None of the haplotypes showed any associations with androgens or insulin-related traits.

SRD5A2

The eight SNPs spanning the SRD5A2 gene were in Hardy-Weinberg equilibrium. Linkage disequilibrium (D') among the eight SNPs ranged from 0.03 to 1.0, with an average D' of 0.80. The patterns of linkage disequilibrium among the SNPs determined three haplotype blocks within the gene (Fig. 2), the first block (block A) comprised of the five SNPs at the 3' end of the gene, the second block (block B) comprised of two SNPs at the 5' end of intron 1, and the third block (block C) consisting of the Val89Leu polymorphism in exon 1. Linkage disequilibrium within block 1 was high, with an average D' of 0.99 (range 0.88 to 1). Linkage disequilibrium between the two SNPs comprising the second block was 1. Table 4 displays the SRD5A2 haplotypes and frequencies.

View larger version (56K): [in this window] [in a new window]   FIG. 2. Gene structure and linkage disequilibrium plot for SRD5A2. The gene structure of SRD5A2 is shown at the top; the gene has five exons and is located on the reverse (minus) strand of chromosome 2. The locations of the genotyped SNPs relative to the exons are indicated. The linkage disequilibrium plot at the bottom displays D' values (percent) for each pair of SNPs in the box at the intersection of the diagonals from each SNP. The dark solid blocks indicate D' = 1 (100%) for the corresponding pair of variants. The three haplotype blocks are indicated.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
This is the first large-scale genetic association study evaluating whether the genes for the two variants of 5-reductase are associated with PCOS and the manifestation of hirsutism within PCOS. A particular haplotype within each gene was associated with an increased frequency of PCOS; alternatively, a coding variant in exon 1 of SRD5A2 was associated with reduced presence of PCOS. Haplotypes in SRD5A1, but not SRD5A2, also were associated with the presence/degree of hirsutism. The only other study to examine either of these genes in hyperandrogenic women performed sequencing of the exons of SRD5A1 in 16 hyperandrogenic women and 16 controls; although several coding variants were discovered, this study was too small to demonstrate association of any of these variants with hyperandrogenism (20).

In contrast to the lack of genetic studies, there have been many physiological studies addressing whether 5-reductase activity is increased in women with PCOS. Given the role of this enzyme in the conversion of testosterone to the more potent DHT, investigators have hypothesized that increased 5-reductase activity contributes to hyperandrogenism in women. Several investigators have found increased levels of serum DHT, serum androstanediol glucuronide, and urinary androsterone, androsterone glucuronide, and 5-androstane-3,17-dione sulfate and/or an increased urinary androsterone to etiocholanone ratio (Fig. 3) in women with PCOS compared with controls, consistent with increased total-body 5-reductase activity in this disorder (5, 6, 7, 8). These physiological studies suggest that the SRD5A1 and SRD5A2 haplotypes associated with PCOS bear functional variants that increase 5-reductase activity. Block C of SRD5A2 consists of a functional variant, discussed in detail below.

View larger version (16K): [in this window] [in a new window]   FIG. 3. Androgen metabolism and 5-reductase activity. The diagram illustrates androgen metabolism with an emphasis on 5-reductase activity. Metabolites in bold indicate androgenic steroids that have undergone 5-reduction. Elevated levels of these metabolites in serum and/or urine have been interpreted as indicative of increased systemic 5-reductase activity. 5R, 5-Reductase activity; 5ßR, 5ß-reductase activity.

Steroid 5-reductase has also been examined in the ovary, where its activity may play a role in the pathogenesis of PCOS. One study analyzing ovarian follicles, stroma, and corpora lutea found only SRD5A1 mRNA in ovarian tissue, but analysis at different pH suggested that both type 1 and type 2 activity were present, with type 1 activity highest in ovarian follicles and type 2 activity highest in corpora lutea (4). A subsequent study found mRNA for both types in the ovary, with higher levels in granulosa cells than theca cells, and higher levels of SRD5A2 mRNA (3). Kinetic analysis demonstrated that 5-reductase activity, primarily type 1, was approximately 4-fold higher in follicles from women with PCOS than controls (3). The investigators suggested that high levels of 5-androstane-3,17-dione in ovarian follicles could contribute to the pathophysiology of PCOS by inhibiting aromatase, resulting in reduced intrafollicular estrogen production and follicular arrest. Consistent with this concept, a study comparing fertile women with polycystic ovaries with infertile women with polycystic ovaries demonstrated higher androstanediol glucuronide levels in the latter, suggesting that increased 5-reductase contributes to infertility in PCOS (29). The fact that both isoforms are expressed in the ovary is consistent with our finding that variation in both genes may be risk factors for PCOS.

A goal of human genetic studies is to identify functional variants that contribute to disease. Genetic markers are known polymorphisms in the genome that are used to track down such disease-causing variants, by virtue of proximity causing them to be inherited together. Although a SNP can serve as a genetic marker, in some instances, its utility is limited by its low information content (only two possible alleles) and ability to mark a limited number of other variants with which it is in linkage disequilibrium. The majority of genetic association studies in PCOS have used single SNPs as markers. Alternatively, a haplotype is a collection of variant alleles inherited together on the same chromosome. Thus, a haplotype tags a whole chromosome segment, capturing variation on a more global scale. Because a disease-altering variant arises on an ancestral haplotype, identification of a haplotype associated with disease should facilitate identification of the functional variant, because it identifies specific chromosomes for subsequent sequencing analysis. Our goal is to bring this haplotype approach to PCOS genetics.

The effects of the associated haplotypes on PCOS were moderate, consistent with the notion that common, complex diseases are genetically influenced by variants in multiple genes, each contributing a modest effect. For example, variation in validated type 2 diabetes genes, such as peroxisome proliferator-activated receptor- (PPARG), only modestly alters risk for type 2 diabetes, with odds ratios ranging from 1.12–1.39 (30). Studies involving thousands of subjects are often required to be able to detect the modest effects typical of susceptibility genes for common conditions (31). Although our cohort is among the largest in PCOS genetics, our results must be replicated by others before SRD5A1 or SRD5A2 are firmly established as genes for PCOS. Any genetic case-control genetic association study may result in false positives because of population stratification; we attempted to mitigate against this by recruiting both cases and controls of the same ethnic group from the same geographic area. One of the goals of reports such as this is to stimulate confirmatory genetic investigations by others as well as initiate experiments to prove the causative nature of the genotype-phenotype associations.

We found that the Leu allele of the Val89Leu polymorphism in SRD5A2 was associated with a reduced frequency of PCOS. The Leu variant appears to reduce 5-reductase activity by 10–40%, as assessed by in vivo 5-reduced metabolite analysis (32, 33) or in vitro studies of enzyme kinetics (34). Kinetic data suggest that position 89 may be at the edge of a substrate-binding region (34). Because prostate cancer is an androgen-dependent neoplasm, many have hypothesized that this variant may modulate cancer risk; however, population genetic studies have provided inconsistent evidence of this (35). On the other hand, in hypospadias, where insufficient androgen action may contribute to underdevelopment of the penis, population genetic studies consistently showed a higher frequency of hypospadias with the lower-activity Leu allele (36, 37). Protection against PCOS with the Leu allele is consistent with its known reduced activity and represents an exciting potential discovery of a functional genetic variant that modulates PCOS risk. The high frequency of the Val allele (70%) may contribute, in part, to the high prevalence of PCOS. This Val allele frequency is similar to that reported for other Caucasian populations (38).

Few studies have demonstrated association of genetic variants with the degree of hirsutism. A likely explanation is the subjective nature of the mFG score. Although intraobserver agreement in mFG scores may be very good (39), comparison of mFG scores conducted by different individuals demonstrates a high degree of variation (40). The noise introduced by interobserver variation would hinder the ability to detect genetic association with mFG score. A major strength of our study was the fact that all mFG scoring was conduced by the same investigator (R.A.), eliminating interobserver variability.

This is the first large-scale genetic association analysis of the 5-reductase genes as candidate genes for PCOS and hirsutism within PCOS. SRD5A1 haplotypes were associated with both PCOS and degree of hirsutism, whereas SRD5A2 haplotypes were associated with PCOS only. These results suggest that 5-reductase activity from either isoform, for example in the ovary, may participate in the pathogenesis of PCOS but that only the type 1 isoform, expressed in hair follicles, has an important effect on the expression of hirsutism. Thus, genetic association data provide insights into the tissue-specific roles of these enzymes and their potential importance in PCOS.

	Footnotes

 
This study was supported in part by the Helping Hand of Los Angeles and by Grants RO1-HD29364 and K24-HD01346 from the National Institutes of Health (to R.A.) and M01-RR00425 (General Clinical Research Center Grant from the National Center for Research Resources).

Disclosure statement: M.O.G., N.A.S., H.J.A., M.P., and X.G. have nothing to declare. R.A. has received consulting fees from Procter & Gamble, Merck & Co., and Organon.

First Published Online July 18, 2006

Abbreviations: BMI, Body mass index; DHEAS, dehydroepiandrosterone sulfate; DHT, dihydrotestosterone; HOMA, homeostasis model assessment; HOMA-%B, HOMA for insulin secretion; HOMA-IR, HOMA for insulin resistance; mFG, modified Ferriman-Gallwey; PCOS, polycystic ovary syndrome; SNP, single-nucleotide polymorphism.

Received February 1, 2006.

Accepted July 7, 2006.

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