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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2006-2600
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 7 2659-2664
Copyright © 2007 by The Endocrine Society

Genes for Enzymes Regulating Dehydroepiandrosterone Sulfonation Are Associated with Levels of Dehydroepiandrosterone Sulfate in Polycystic Ovary Syndrome

Mark O. Goodarzi, Heath J. Antoine and Ricardo Azziz

Division of Endocrinology, Diabetes and Metabolism, Departments of Medicine (M.O.G., H.J.A.), and Obstetrics and Gynecology (M.O.G., R.A.), and Medical Genetics Institute (M.O.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 Obstetrics and Gynecology, 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: The adrenal androgen (AA) metabolite dehydroepiandrosterone sulfate (DHEAS) is often elevated in women with polycystic ovary syndrome (PCOS); AA excess in PCOS appears to be, in part, a heritable trait. Dehydroepiandrosterone (DHEA) sulfonation is controlled by the enzymes DHEA sulfotransferase (SULT2A1) and steroid sulfatase (STS). Polymorphisms in these genes have not been evaluated as modulators of DHEAS level in PCOS.

Objective: The aim was to test the hypothesis that variants in the SULT2A1 and STS genes are associated with DHEAS levels in women with PCOS.

Design: Women with and without PCOS were genotyped for seven single nucleotide polymorphisms (SNPs) in SULT2A1 and seven SNPs in STS. SNPs and haplotypes were determined and tested for association with DHEAS.

Setting: Subjects were recruited from the reproductive endocrinology clinic at the University of Alabama at Birmingham; controls were recruited from the 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 in the study.

Main Measurements: SULT2A1 and STS genotype and DHEAS levels were measured.

Results: In women with PCOS, SNP rs182420 in SULT2A1 was associated with DHEAS (P = 0.0035). Two haplotypes carrying the minor allele of rs182420 were also associated with DHEAS (P = 0.04 each). Variants within STS were not associated with DHEAS level. No associations were observed in control women.

Conclusion: This study presents genetic evidence suggesting a potential role of SULT2A1, but not STS, in the inherited AA excess of PCOS.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
FAMILIAL AND TWIN studies have suggested that polycystic ovary syndrome (PCOS) is a complex, common genetic disorder, such that multiple susceptibility genes interact with lifestyle and environmental factors to result in disease (1, 2). Not only do genetic factors contribute to PCOS risk, but component traits of PCOS, such as insulin resistance and testosterone level, also appear to be modulated by inherited factors (3).

PCOS is principally a disorder of ovarian androgen excess; however, in most patients the adrenal glands also contribute to the hyperandrogenemia. Dehydroepiandrosterone sulfate (DHEAS), a metabolite of the adrenal androgen (AA) dehydroepiandrosterone (DHEA), is produced almost exclusively by the adrenal cortex and is considered a marker of AA production. Approximately 25% of PCOS women have supranormal levels of DHEAS, although the mean levels of DHEAS are shifted upward in most patients with the disorder (4). The sulfonation of DHEA occurs through the action of DHEA sulfotransferase (SULT2A1), mainly in the adrenal cortex. In turn, the sulfonate group (SO3–) in DHEAS is removed by steroid sulfatase (STS), an enzyme that is expressed in many tissues, regenerating DHEA that can then be metabolized to active androgens or estrogens.

Initial evidence that DHEAS was under genetic control in PCOS was presented in a study documenting elevated DHEAS levels in brothers of women with PCOS (5). Our study of women with PCOS and their sisters also documented a heritability for DHEAS of approximately 45% (6). Extra-adrenal factors such as insulin levels and ovarian androgens and estrogens appear to have limited impact on DHEAS levels (7, 8, 9, 10, 11), further supporting the concept that intrinsic, inherited factors regulate AA excess in PCOS.

Given that evidence suggests that AA excess is an inherited component phenotype in PCOS, we hypothesized that variants in genes for the enzymes most directly responsible for modulating DHEAS levels, SULT2A1 and STS, would be associated with circulating DHEAS levels in PCOS. We analyzed single nucleotide polymorphisms (SNPs), as well as haplotypes in these genes, to capture common variation across the entirety of the genes. We found that variation in SULT2A1, but not STS, was associated with DHEAS in women with PCOS.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects and phenotyping

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, AL, area. All subjects were unrelated. Clinical characteristics of these subjects are presented in Table 1Go.


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  		TABLE 1. Clinical characteristics

 
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, including oral contraceptives, for at least 3 months; and meeting diagnostic criteria for PCOS). To ensure the inclusion of women with the classic disorder, the presence of PCOS was defined by the 1990 National Institutes of Health consensus criteria (12), including: 1) clinical hyperandrogenism and/or hyperandrogenemia; 2) oligo-ovulation; 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 (13). Of the 287 women with PCOS, 34 (12%) had elevation in DHEAS, but not in free or total testosterone. Of these 34 subjects, 25 had hirsutism. Thus, of the entire cohort, nine women (3%) received a diagnosis of PCOS based on elevated DHEAS as the only hyperandrogenic manifestation.

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, or alopecia, or endocrine dysfunction. Controls were recruited by word of mouth and advertisements in the Birmingham, AL, area, through a call for "healthy women," without detailing further the nature of the studies.

The comprehensive physical examination and hormonal evaluation of these subjects have been previously described in detail (13). Levels of DHEAS were obtained between d 3 and 8 (follicular phase) after a spontaneous menstrual cycle or progesterone-induced withdrawal bleed. The same laboratory assays were used for all subjects. Completeness of data was 98.6%.

All subjects 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.

Genotyping and haplotype determination

We selected seven SNPs, rs182420, rs17464626, rs2547238, rs2547231, rs11083906, rs2932766, and rs7508610, which span the 15.7-kb genomic length of SULT2A1. These were selected because they are predicted to tag the haplotypes (across the entire gene, plus 5 kb upstream and 3 kb downstream) occurring at more than 1% frequency in the Caucasian population of the HapMap database (14). Seven SNPs (rs2072326, rs5934700, rs5934770, rs12861247, rs4403552, rs17268988, and rs6639825) across the 135 kb STS gene were chosen to tag the common haplotypes across the entire gene in the Caucasian population of the HapMap database. The 14 SNPs were genotyped using the 5'-exonuclease assay (TaqMan MGB; Applied Biosystems, Foster City, CA) described previously (15, 16); duplicate genotyping of 96 samples for one SNP yielded 100% concordance. The PCR primers and TaqMan MGB probes are presented in Table 2Go. The genotyping success rate was 94.4%.


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  		TABLE 2. Primers and probe sequences used in the 5'-exonuclease assay

 
Haploview 3 (17) was used to determine haplotypes as well as haplotype blocks. Haploview constructs haplotypes using an accelerated expectation maximization algorithm similar to the partition/ligation method (18), which creates accurate population frequency estimates of the phased haplotypes based on the maximum likelihood derived from the unphased input genotypes. Haploview was used to calculate linkage disequilibrium (the D’ statistic) between each pairwise combination of all the SNPs within each gene. Haploview is able to determine haplotype blocks using different block partition algorithms or user-defined blocks (17). Because the various algorithms gave slightly different haplotype blocks, we chose to consider blocks spanning the entirety of each gene. Haplotypes were assigned to individual subjects only when the assignment could be made with a greater than 95% certainty.

Statistical analysis

Unpaired t and {chi}2 tests were used to compare clinical characteristics between women with and without PCOS; quantitative trait values were log or square-root transformed as appropriate to reduce nonnormality.

For all genetic association analyses, DHEAS values were square-root transformed to reduce nonnormality. SNPs and haplotypes were the genotypic units used in association analyses. Haplotypes were assigned before association analyses. Association with DHEAS was evaluated using analysis of covariance, adjusting for age and body mass index (BMI) by including both of them as independent variables in every analysis. Association with the presence/absence of PCOS was evaluated using logistic regression, again adjusting for age and BMI. Significance was taken as P < 0.05. Nominal P values are reported as well as P values corrected using a Bonferroni adjustment (considering the number of SNPs or haplotypes analyzed in each gene). Analyses were carried out using Statview 5.0 (SAS Institute, Cary, NC).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
We genotyped seven SNPs spanning the SULT2A1 gene (Table 3Go and Fig. 1Go). All markers except rs17464626 were in Hardy-Weinberg equilibrium; this marker was not used for association analysis or haplotype construction. Linkage disequilibrium (D’) among the remaining SNPs in our subjects ranged from 0.35–1.0, with an average D’ of 0.83. The overall high degree of linkage disequilibrium confirmed the possibility of constructing haplotypes across the entire gene. Table 4Go displays the SULT2A1 haplotypes and their frequencies. The haplotypes observed in our white subjects matched those predicted for Caucasians in HapMap, differing only moderately in frequency. The six haplotypes of frequency more than 5% were tested for association with DHEAS.


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  		TABLE 3. Frequency and location information on SULT2A1 and STS variants

 

Figure 1
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  		FIG. 1. Gene structure and linkage disequilibrium plot for SULT2A1. The gene structure of SULT2A1 is shown at the top; the gene has six exons and is located on the reverse strand of chromosome 19 (19q13.3). The locations of the genotyped SNPs relative to the exons are indicated. The linkage disequilibrium plot at the bottom displays D' values (%) 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 SNPs were considered together in one haplotype block as indicated.

 

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  		TABLE 4. SULT2A1 and STS haplotypes and haplotype frequencies

 
Of women with PCOS, carriers of the minor G allele of SNP rs182420 had lower DHEAS levels than subjects homozygous for the A allele (G carriers: median DHEAS 1899.5 ng/ml, A homozygotes: 2158.0 ng/ml; nominal P = 0.0035; Bonferroni-corrected P = 0.021). The two haplotypes carrying the G allele were each also associated with a trend (not significant after Bonferroni correction) toward reduced DHEAS levels; GCGCTG haplotype carriers had a median DHEAS of 1686.0 vs. 2141.0 ng/ml for noncarriers (nominal P = 0.045; Bonferroni-corrected P = 0.27). Carriers of haplotype GCTTTG had a median DHEAS of 2069.0 vs. 2090.0 ng/ml in noncarriers (nominal P = 0.042; Bonferroni-corrected P = 0.25). Of control women, rs182420 was not associated with DHEAS level (nominal P = 0.5), and no SULT2A1 haplotype was associated with DHEAS. These variants were not associated with a risk of PCOS.

The seven SNPs spanning the STS gene were in Hardy-Weinberg equilibrium (Table 3Go and Fig. 2Go). Linkage disequilibrium (D’) among the seven SNPs ranged from 0.69–1.0, with an average D’ of 0.96. Given the high degree of linkage disequilibrium, a haplotype block was formed containing all SNPs across the gene. Table 4Go displays the STS haplotypes and frequencies. None of the STS SNPs or haplotypes was associated with DHEAS level in women with or without PCOS, or with PCOS risk.


Figure 2
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  		FIG. 2. Gene structure and linkage disequilibrium plot for STS. The gene structure of STS is shown at the top; the gene has 10 exons and is located on the forward strand of the X chromosome (Xp22.32). The locations of the genotyped SNPs relative to the exons are indicated. The linkage disequilibrium plot at the bottom displays D' values (%) 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 SNPs were considered together in one haplotype block as indicated.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This is the first large-scale genetic association study evaluating whether the genes regulating DHEA sulfonation are associated with DHEAS level in women with PCOS. A particular SNP within the SULT2A1 gene, as well as the haplotypes defined by the minor allele of this SNP, were associated with lower DHEAS levels in PCOS; alternatively, no variants in STS were associated with DHEAS levels in these women. Variants in these two genes were not associated with DHEAS level in controls and were not associated with a risk of PCOS itself.

Although the ovaries are typically considered the main source of androgens in PCOS, evidence exists that the adrenal cortex also contributes to excess androgen production. The measurement of circulating levels of the AA metabolite DHEAS is considered a useful marker of AA secretion (and excess) because this metabolite is: 1) 97–99% of adrenocortical origin, 2) the most abundant steroid, 3) relatively stable throughout the day and menstrual cycle, and 4) easily measured. Thus, we and others used circulating DHEAS level as a populational marker of AA excess. Previous reports (19, 20, 21, 22) indicated that serum levels of DHEAS were above the normal limit in 40–60% of patients with PCOS. However, using racial and age normative values, we determined the prevalence of absolute (i.e. >95th percentile of normal) DHEAS excess to be 20–30% (4). Nevertheless, these studies also demonstrated a generalized upward shift in DHEAS values in PCOS women, compared with controls.

Studies in subjects with and without PCOS have suggested that genetic factors contribute to variability in DHEAS levels. In non-PCOS populations, studies of twins or families documented heritability indexes for DHEAS of 40–60% (23, 24, 25, 26), indicating that 40–60% of the variability is due to inherited factors. Of note, one study (27) found that DHEAS was more heritable in women than men, which may be relevant to PCOS. Our study (6) of 62 women with PCOS and 69 of their sisters revealed a heritability of DHEAS of approximately 45%; of note, hormone use by the sisters had minimal impact on the heritability estimate, further evidence that genetic and not environmental factors are important regulators of variability in DHEAS. The brothers (n = 119) of 87 unrelated PCOS women had significantly elevated DHEAS levels compared with control men, and a positive linear relationship between DHEAS in probands and their brothers was observed (5).

Given the aforementioned evidence supporting the inherited basis of DHEAS, combined with the concept of PCOS as a genetic disorder, we and other investigators have searched for genes that determine DHEAS level in PCOS. We did not find any role for genetic variation in CYP17, the gene encoding P450c17, or insulin receptor substrate-1 in determining DHEAS level in PCOS (28, 29). The gene for 11-ß hydroxysteroid dehydrogenase type 1 has been implicated in cortisone reductase deficiency, a condition resembling PCOS. In this condition, impaired regeneration of cortisol from cortisone is thought to lead to increased pituitary adrenocorticotropic hormone secretion, resulting in secondary AA excess. An 11-ß hydroxysteroid dehydrogenase type 1 variant implicated in cortisone reductase deficiency was associated with higher DHEAS levels in women with PCOS in one study (30), but not another (31). It is apparent that only a small number of candidate gene investigations have been carried out for association with DHEAS level in PCOS. An analysis of the genes responsible for the addition and removal of the sulfonate group to DHEA was a logical choice.

Our results that SULT2A1 variants, but not STS variants, were associated with DHEAS level in PCOS are consistent with the physiology of these enzymes. STS is widely expressed throughout the body, which allows diverse tissues to produce DHEA from DHEAS for use as an androgenic and/or estrogenic precursor (32). Examples of tissues expressing sulfatase activity include liver, ovary, testis, adrenals, placenta, prostate, skin, brain, viscera, endometrium, aorta, kidney, bone, and peripheral blood lymphocytes. STS activity in various sites is thought to participate in hormone-dependent breast cancer, desquamation of skin, immune system modulation, bone formation, and neurological and reproductive function (32). The diversity of sites of expression and function strongly suggest that STS undergoes differential regulation in different tissues; such tissue-specific regulation is likely to override any mild changes in enzyme level or activity that may be mediated by common inherited variation.

Alternatively, sulfonation of DHEA to DHEAS occurs almost exclusively in the zona reticularis of the adrenal cortex, where SULT2A1 is highly expressed (33). SULT2A1 is also expressed at significant levels in the liver; however, its function at this site is sulfonation of bile acids and dietary xenobiotics and drugs (34). Thus, in contrast to the widespread sulfatase activity, the SULT2A1 activity is restricted to one tissue. In this case, inherited variation with a moderate effect on enzyme levels or activity would be expected to have an impact on circulating DHEAS levels.

The SULT2A1 variant that was associated with DHEAS levels in women with PCOS displayed no association in control women and was neutral in terms of PCOS risk. This suggests that genetic variation in SULT2A1 may not predispose to PCOS in general but, rather, is a modifier of the PCOS phenotype (AA excess) in affected women. This likely represents a complex interaction between SULT2A1 genotype, and the genetic and physiological context of affected, but not unaffected, women.

In our analyses of genetic association with DHEAS, we considered key physiological covariates that are known to be related to DHEAS level. DHEAS levels are well known to decrease with age. Notably, inclusion of age as a covariate in our analyses increased the significance of the association of rs182420 with DHEAS (data not shown), indicating the need to adjust for age in association analyses with DHEAS. Our in vitro study of adrenal tissue suggested that insulin may up-regulate SULT2A1 and/or down-regulate STS (11). Fasting insulin was obtained in approximately 70% of the subjects. Inclusion of fasting insulin as a covariate, along with age and BMI, did not alter the significance of the rs182420 association (nominal P = 0.0025) in women with PCOS.

We analyzed haplotypes as markers that encompass common variation across broad regions. In the case of SULT2A1, the haplotype associations observed did not add any additional information over the SNP result. The minor G allele of rs182420 and both haplotypes carrying this allele were associated with lower DHEAS. The haplotype associations were of lower statistical significance because of the split of the G carriers into two smaller groups (carriers of the two haplotypes). Either the G allele is in a regulatory site that affects expression of SULT2A1, or it is in linkage disequilibrium with an unknown functional variant elsewhere in the gene. For STS, lack of association of any haplotypes with DHEAS provides confidence in the negative result because of the comprehensive coverage of the gene. This is in contrast to negative studies of candidate genes wherein only one SNP was examined.

Although genetic association studies provide evidence that a particular gene may influence a particular phenotype, they do not constitute proof of causation. Any genetic association study may produce false-positive results; we mitigated against this by recruiting subjects from a single ethnic group from the same geographic area, and using a uniform and comprehensive phenotyping protocol. We hope that this study encourages others to attempt replication of association of SULT2A1 association with DHEAS levels in PCOS, preferably with cohorts of similar or greater numbers of subjects. This report may also stimulate physiological or in vitro studies examining the role of SULT2A1 in PCOS.

In summary, this is the first large-scale genetic association analysis of the SULT2A1 and STS genes as candidate genes for DHEAS in PCOS. SULT2A1 variants were associated with DHEAS level in women with PCOS, while STS variants were not. These results suggest that inherited variation in SULT2A1 activity may modulate the severity of AA excess in PCOS. Alternatively, inherited variability in STS activity appears not to play a major role in determining DHEAS level. Thus, genetic association data provide insights into the roles of these enzymes as genetic modifiers of the PCOS phenotype. These results may also have relevance for inherited regulation of steroidogenesis in general.


   Footnotes
 
This work was supported in part by NIH Grants RO1-HD29364 and K24-HD01346 (to R.A.), and M01-RR00425 (General Clinical Research Center Grant from the National Center for Research Resources), and an endowment from the Helping Hand of Los Angeles, Inc.

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

First Published Online April 10, 2007

Abbreviations: AA, Adrenal androgen; BMI, body mass index; DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate; PCOS, polycystic ovary syndrome; SNP, single nucleotide polymorphism; STS, steroid sulfatase; SULT2A1, dehydroepiandrosterone sulfotransferase.

Received November 27, 2006.

Accepted April 4, 2007.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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M. O. Goodarzi, N. Xu, and R. Azziz
Association of CYP3A7*1C and Serum Dehydroepiandrosterone Sulfate Levels in Women with Polycystic Ovary Syndrome
J. Clin. Endocrinol. Metab., July 1, 2008; 93(7): 2909 - 2912.
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