Molecular Human Reproduction, Vol.18, No.6 pp.

320– 324, 2012

Advanced Access publication on January 10, 2012 doi:10.1093/molehr/gas002

ORIGINAL ARTICLE

Association study of CYP17 and

HSD11B1 in polycystic ovary syndrome
utilizing comprehensive gene coverage
Angela K. Chua 1, Ricardo Azziz 2,4, and Mark O. Goodarzi 1,3,*
1
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Blvd.,
Room B-131, Los Angeles, CA 90048, USA 2Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles,
CA 90048, USA 3Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA

*Correspondence address. Tel: +1-310-423-4774; Fax: +1-310-423-0440; E-mail: mark.goodarzi@cshs.org

Submitted on November 28, 2011; resubmitted on January 1, 2012; accepted on January 4, 2012

abstract: Cytochrome P450-C17 enzyme (CYP17) is an important component of the androgen synthesis pathway, a pathway that is
dysfunctional in polycystic ovary syndrome (PCOS). Variation in 11-beta hydroxysteroid dehydrogenase (HSD11B1) is associated with cor-
tisone reductase deficiency, a condition with a phenotype similar to PCOS. Both CYP17 and HSD11B1 genes have been previously studied
for their possible relationship with PCOS, yielding inconsistent results. In this study, we evaluated the association between variation in these
genes and PCOS. Two-hundred and eighty-seven Caucasian PCOS women and 187 Caucasian controls were genotyped for single nucleotide
polymorphisms (SNPs) that were specifically chosen to allow full coverage of CYP17 and HSD11B1, including four SNPs in CYP17 and eight
SNPs in HSD11B1. SNP and haplotype association analyses were conducted. Our results indicate that variants in the two genes are not
associated with PCOS, or with the quantitative traits characteristic of PCOS, suggesting that these genes are not major risk factors for
the syndrome.
Key words: CYP17 / haplotype / HSD11B1 / polycystic ovary syndrome / single nucleotide polymorphism

Investigators searching for PCOS genes have also looked to corti-

Introduction
Polycystic ovary syndrome (PCOS), characterized by hyperandrogen-
ism, oligo-ovulation and polycystic ovarian morphology, is a leading
cause of infertility and affects 7% of women (Goodarzi and Azziz,
2006). Evidence for a genetic basis for the hyperandrogenemia of
PCOS is found in the increased rates of hyperandrogenemia in the
family members of PCOS probands, both with and without PCOS
(Legro et al., 1998). In an effort to identify the genetic basis of
PCOS, a number of genes encoding major enzymes of the androgen
biosynthetic pathway have been examined and associations reported,
although the support for these associations in replication studies has
not been unanimous (Goodarzi, 2008). One such candidate gene is
CYP17, which codes for the cytochrome P450 enzyme that catalyzes
the addition of a hydroxyl group at carbon 17 of the steroid D ring
of pregnenolone and progesterone to produce 17-hydroxypregneno-
lone and 17-hydroxyprogesterone, respectively (Gilep et al., 2011).
It also has a lyase activity, acting to convert 17-hydroxyprogesterone
and 17-hydroxypregnenolone to androstenedione and dehydroepian-
drosterone (DHEA), respectively.
4
Present address: Departments of Obstetrics and Gynecology, and Department of Medicine, Medical College of Georgia, Georgia Health Sciences University, Augusta, GA 30912, USA.
sone reductase deficiency (CRD), a condition that is partly attributed
to a decrease in 11b hydroxysteroid dehydrogenase (11b-HSD1)
activity. HSD11B1 is a keto reductase, whose function is to reduce
cortisone to cortisol in the liver; a decrease in its activity leads to
adrenal hyperandrogenism via the compensatory elevation of adreno-
corticotropic hormone (Draper et al., 2003). The phenotype of CRD
is in some ways similar to that of PCOS and includes traits such as
hirsutism, oligo-amenorrhea and infertility in women, raising interest
in the possible involvement of HSD11B1 in PCOS.
In this study, we investigated the association of CYP17 and
HSD11B1 SNPs and haplotypes with PCOS susceptibility and with
biochemical features of subjects with PCOS in a well-characterized
cohort of Caucasian PCOS and control subjects.
Materials and Methods
Subjects and phenotyping
A total of 287 consecutive unrelated non-Hispanic White women with
PCOS and 187 unrelated White control women were recruited from
the Birmingham, AL, USA area as previously described (Goodarzi et al.,

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CYP17 and HSD11B1 variants in PCOS 321

2006). Clinical characteristics are given in Table I. PCOS was diagnosed common haplotypes of the region for HSD11B1. SNP rs12086634
using the 1990 National Institutes of Health criteria (Zawadzki and (1971T/G) has been implicated in CRD (Draper et al., 2003). These 12
Dunaif, 1992). The comprehensive physical examination and hormonal SNPs capture 34 of 37 (92%) of the CEU HapMap SNPs at r 2 . 0.8 for
evaluation of these subjects have been previously described in detail the two genes.
(Azziz et al., 2004). All subjects gave written informed consent, and the
study was performed according to the guidelines of the Institutional
Statistical analysis
Review Boards of University of Alabama and Cedars-Sinai Medical Center.
Haploview 4.2 (Barrett et al., 2005) was used to determine haplotypes as
well as haplotype blocks, using the solid spine of LD algorithm. SNPs and
Single nucleotide polymorphisms genotyping haplotypes were tested for association with PCOS diagnosis and compo-
and haplotype determination nent phenotypes of PCOS. Associations of genotype with PCOS were
evaluated using logistic regression. Associations with androgens, the modi-
Single nucleotide polymorphisms (SNPs) were selected using frequency and
fied Ferriman-Gallwey (mFG) score and insulin-related traits were evalu-
validation data from the CEU (Utah residents with ancestry from northern
ated using analysis of covariance in the PCOS women. All analyses were
and western Europe) population of the International HapMap database
adjusted for age and BMI. Significance was taken at P , 0.008 to
(release 24; http://hapmap.ncbi.nlm.nih.gov/) (The International HapMap
account for the effects of multiple testing, considering that we analyzed
Consortium, 2003) with the aim of exploiting linkage disequilibrium (LD)
one LD group of SNPs from each of two genes (CYP17 and HSD11B1)
to capture the common haplotypes in these genes. CYP17 maps to chromo-
against three families of traits (PCOS diagnosis, androgenic traits and
some 10q24.3 and spans 6.9 kb. HSD11B1 maps to chromosome 1q32–
metabolic traits), yielding a correction factor of six (0.05/6 ¼ 0.008).
q41 and spans 30 kb. Genotyping of SNPs was by the 5′ -exonuclease
assay (Taqman MGB, Applied Biosystems, Foster City, CA, USA) as previ-
ously described (Livak, 1999; Goodarzi et al., 2003). SNPs rs10883783,
rs1004467, rs6162 (Ser65Ser) and rs743572 were selected to represent
the common haplotypes of the region for CYP17. SNP rs743572 is the
– 34 C/T promoter SNP examined in several prior studies (Diamanti-
Kandarakis et al., 1999; Marszalek et al., 2001; Kahsar-Miller et al., 2004;
Echiburu et al., 2008; Park et al., 2008; Pusalkar et al., 2009; Unsal et al.,
2009). SNPs rs12086634, rs2236902, rs2282739, rs11119328, rs846906,
rs11808690, rs6672256 and rs12060922 were selected to represent the

Table I Clinical characteristics of the study cohort.

Control PCOS (n 5 287)

(n 5 187)
........................................................................................
Age (years) 33.0 (17.0) 27.5 (11.5)a
BMI (kg/m2) 24.1 (6.4) 34.7 (13.5)a
WHR 0.78 (0.08) 0.83 (0.10)a
mFG score 0 (0) 7.0 (5.0)a
Hirsute (%) 0 73.9a
Total testosterone (nmol/l) 1.42 (0.92) 2.77 (1.07)a
b
Free testosterone (pmol/l) 12.1 (9.0) 29.1 (16.3)a
DHEAS (mmol/l) 2.58 (2.03) 5.66 (4.61)a
b
SHBG (nmol/l) 220.0 (120.0) 150.0 (70.0)a
Insulin (pmol/l) 49.5 (45.9) 129.2 (129.2)a
Glucose (mmol/l) 4.77 (0.56) 4.77 (0.72)
HOMA-IR 0.92 (0.83) 2.29 (1.93)a
Figure 1 Gene structure and LD plot for the cytochrome P450-
HOMA-%B 103.9 (59.5) 175.3 (99.3)a
C17 (CYP17) gene. The gene structure is shown at top, with exons
BMI, body mass index, WHR, waist-to-hip ratio; mFG, modified Ferriman-Gallwey shown as filled boxes and introns as connecting lines. The locations
hirsutism score; DHEAS, dehydroepiandrosterone sulfate; SHBG, sex of the genotyped SNPs relative to the exons are indicated. The LD
hormone-binding globulin; HOMA-IR, insulin resistance estimated by the plot at the bottom displays D′ values (%) for each pair of SNPs in
homeostatic model assessment; HOMA-%B, beta-cell function estimated by the
the box at the intersection of the diagonals from each SNP. The
homeostatic model assessment.
Data are presented as median (interquartile range). Fasting insulin, glucose and solid blocks indicate D′ ¼ 1 (100%) for the corresponding pair of var-
HOMA variables were available in a subset (70%) of the cohort, all of whom were iants [all logarithm of the odds (LOD) scores ≥2 for the correspond-
non-diabetic. ing pair of variants; the LOD score compares the likelihood of
a
b
P , 0.001 compared with control group. obtaining the D′ value if the two SNPs are linked, to the likelihood
SHBG activity was measured by competitive-binding analysis, using Sephadex G-25
and [3H]T as the ligands; free testosterone was calculated as previously described
of observing the same D′ purely by chance; a LOD score of 2 indi-
(Boots et al., 1998). This assay gives SHBG values of 100 –300 nmol/l in normal cates a 100-fold likelihood]. Within the gene, SNPs were considered
adult women. together in one haplotype block as indicated.
322 Chua et al.

The sample size of 287 cases and 187 controls has an excellent power
(≥90%) to detect the association of risk alleles of frequency ≥0.2 with
PCOS at an odds ratio ≥2.0 and a fair-to-good power (40 – 90%) to
detect the association at odds ratios 1.5 and 1.75. Detailed power calcula-
tions given in the Supplementary data, Table SI reveal a lower power to
detect the association of rare risk alleles (frequency ≤0.1) with PCOS
at an odds ratio ,1.75.
Results
CYP17
We genotyped four SNPs in CYP17 (Fig. 1). SNP frequencies are
shown in Table II. A strong LD (D′ ¼ 1) was observed between
each pair of CYP17 SNPs. None of the CYP17 SNPs or haplotypes
were associated with PCOS diagnosis or with component quantitative
traits of PCOS [free or total testosterone, DHEA sulfate, sex
hormone-binding globulin, mFG score, fasting glucose, fasting insulin
or homeostatic model assessments of insulin resistance (HOMA-IR)
and beta-cell function (HOMA-%B)]. The common haplotypes for
CYP17 are displayed in Table III.
HSD11B1
We genotyped eight SNPs spanning HSD11B1 (Fig. 2). SNP frequen-
cies are displayed in Table II. LD among markers (D′ ) in HSD11B1
ranged from 0.18 to 1.0 (an average pairwise D′ of 0.93). None of
the HSD11B1 SNPs or haplotypes were associated with PCOS
susceptibility or with component quantitative traits of PCOS. The
common haplotypes are displayed in Table III.
Discussion
In this study we did not observe association between polymorphisms
in the HSD11B1 and CYP17 gene regions and PCOS risk or
quantitative traits of PCOS, despite the predicted effect of these
genes on androgen levels.
Although hyperandrogenism is a distinct feature of PCOS, studies of
CYP17, which encodes the rate-limiting step in androgen synthesis,
have yielded mixed results, which could have resulted from smaller
sample sizes in those studies and the fact that most prior studies
looked at only one or two variants per gene. Most studies focused
almost exclusively on a variant in the 5′ promoter region (234 T/C,
rs743572). While a few studies reported an association of this
variant with PCOS (Diamanti-Kandarakis et al., 1999; Pusalkar et al.,
2009) or polycystic ovarian morphology (Carey et al., 1994), several
others found no such association (Gharani et al., 1996; Liovic et al.,
1997; Techatraisak et al., 1997; Marszalek et al., 2001; Park et al.,
2008; Unsal et al., 2009).
Regarding quantitative traits, the CYP17 promoter variant has been
associated with androgen levels (Diamanti-Kandarakis et al., 1999;
Perez et al., 2008; Pusalkar et al., 2009), adiposity and insulin levels
(Echiburu et al., 2008) in some studies; alternatively, other investiga-
tors found no association with androgen levels (Gharani et al., 1996;
Techatraisak et al., 1997; Marszalek et al., 2001; Kahsar-Miller et al.,
2004; Unsal et al., 2009). Only one study employed a haplotype
approach, genotyping seven CYP17 SNPs including rs743572 in
Korean subjects; while in this study no SNP associations were
observed, one haplotype was found to be associated with PCOS
(Park et al., 2008). Studies with negative association results tended
to have larger sample sizes than those that had positive association
results, decreasing the chances of false positives. For example, an
early positive study (Carey et al., 1994) was found to have negative
results when the sample size was expanded (Gharani et al., 1996).
Our current negative results appear to be consistent with the
balance of prior reports.
Most association studies of HSD11B1 in PCOS arrived at the same
conclusion as the present report. HSD11B1 was selected as a candi-
date gene given the resemblance of the CRD phenotype to PCOS.
One study found that the CRD-associated rs12086634 polymorphism

Table II MAF and position information on CYP17 and HSD11B1 SNPs.

SNP designation Variation Location in gene Overall frequency PCOS frequency Control frequency
.............................................................................................................................................................................................
CYP17
rs10883783 T/A Intron 7 0.323 0.331 0.310
rs1004467 T/C Intron 3 0.096 0.096 0.094
rs6162 G/A Exon 1 0.448 0.460 0.428
rs743572 A/G 5′ region 0.420 0.429 0.407
HSD11B1
rs12086634 T/G Intron 3 0.202 0.197 0.211
rs2236902 A/G Intron 4 0.017 0.014 0.020
rs2282739 C/T Intron 4 0.237 0.238 0.237
rs11119328 C/A Intron 4 0.170 0.165 0.177
rs846906 C/T Intron 4 0.179 0.178 0.180
rs11808690 T/G Intron 4 0.200 0.196 0.208
rs6672256 T/A Intron 4 0.191 0.189 0.193
rs12060922 G/A Intron 4 0.211 0.210 0.213

Note: MAF, minor allele frequency. Allele frequency data are from genotyping of 474 subjects. CYP17, cytochrome P450-C17 gene. HSD11B1, 11-beta hydroxysteroid dehydrogenase gene.
CYP17 and HSD11B1 variants in PCOS 323

Table III CYP17 and HSD11B1 haplotypes and haplotype frequencies.

Designation Haplotype Overall frequency PCOS frequency PCOS counta Control frequency Control counta
.............................................................................................................................................................................................
CYP17
1 TTGA 0.557 0.547 307 0.572 199
2 ATAG 0.322 0.332 186 0.307 107
3 TCAG 0.097 0.096 54 0.097 34
4 TTAA 0.024 0.025 14 0.024 8
HSD11B1
1 TACCCTTG 0.574 0.575 317 0.574 198
2 TACCTTTG 0.178 0.176 97 0.181 62
3 GATACGAA 0.168 0.163 90 0.177 61
4 TATCCTTG 0.019 0.024 13 0.010 4
5 TGTCCTTG 0.017 0.014 8 0.020 7
6 GATCCGTA 0.016 0.015 9 0.016 6
7 GATCCGAA 0.015 0.017 10 0.012 4

Note: CYP17 haplotypes are composed of SNPs rs10883783, rs1004467, rs6162 and rs743572. HSD11B1 haplotypes are composed of SNPs rs12086634, rs2236902, rs2282739,
rs11119328, rs846906, rs11808690, rs6672256 and rs12060922.
a
Count represents the number of chromosomes assigned a particular haplotype by the expectation maximization algorithm.

in HSD11B1, which we included in our study, was associated with

Figure 2 Gene structure and LD plot for the 11-beta hydroxyster-
oid dehydrogenase (HSD11B1) gene. The gene structure is shown at
top, with exons shown as filled boxes and introns as connecting lines.
The locations of the genotyped SNPs relative to the exons are indi-
cated. The LD 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 solid blocks indicate D′ ¼ 1 (100%) for the corre-
sponding pair of variants. The red blocks indicate a logarithm of the
odds (LOD) score ≥2 for the corresponding pair of variants; blue
or white solid blocks indicate a LOD score ,2. The LOD score com-
pares the likelihood of obtaining the D′ value if the two SNPs are
linked, to the likelihood of observing the same D′ purely by chance;
a LOD score of 2 indicates a 100-fold likelihood. Within the gene,
SNPs were considered together in one haplotype block as indicated.
hyperandrogenism in lean PCOS patients and may also prevent
obesity in these patients (Gambineri et al., 2006). Limitations of that
study were the abundance of lean PCOS subjects and the lack of
power in identifying the same association in the controls. A subse-
quent study by the same group found that HSD11B1 variants were
not associated with PCOS; rather HSD11B1 variation was associated
with a higher risk of metabolic syndrome in the general population, re-
gardless of the diagnosis of PCOS (Gambineri et al., 2011). Additional
HSD11B1 studies support our negative association result, such as one
study examining the HSD11B1 83557insA mutation and its possible
association with PCOS (San Millan et al., 2005) and another study
seeking to find a possible connection between CRD-associated
HSD11B1 variants and PCOS susceptibility (Draper et al., 2006).
We believe that our results bring clarity to the conflicting literature
concerning the role of CYP17 and HSD11B1 in PCOS. Our compre-
hensive approach using haplotype techniques, allowing us to cover
the entire gene region, increases confidence that these genes do not
play an important role in PCOS. Also, our larger sample size com-
pared with several prior studies reduced the chance of false positive
results, as did our use of a P value cutoff corrected for multiple
testing. Given these advantages of our study, we conclude that
genetic variation in the CYP17 and HSD11B1 loci are not major risk
factors for PCOS.
Supplementary data
Supplementary data are available at http://molehr.oxfordjournals.org/.
Authors’ roles
A.K.C. contributed to writing the manuscript. A.K.C. and M.O.G.
contributed to the genetic association analysis. R.A. and M.O.G.
324
contributed to design of the study and editing of the manuscript. R.A.
contributed to recruitment of study subjects.
Funding
This work was supported by the National Institutes of Health
[HD029364 to R.A. and DK079888 to M.O.G., CTSI Grant
UL1RR033176]; the Helping Hand of Los Angeles, Inc. and the
Winnick Clinical Scholars Award [to M.O.G].
Conflict of interest
None declared.
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