Association of SRD5A2 Variants and Serum
Androstane-3,17-Diol Glucuronide Concentration in
Chinese Elderly Men
Jieying Jiang,
1
Nelson L.S. Tang,
1,2*
Claes Ohlsson,
3
Anna L. Eriksson,
4
Liesbeth Vandenput,
4
ChenDi Liao,
1
Xingyan Wang,
1
Frank W.K. Chan,
5
Anthony Kwok,
6
Eric Orwoll,
7
Timothy C.Y. Kwok,
8
Jean Woo,
8,9
and
Ping Chung Leung
6
BACKGROUND: Results of recent studies have demon-
strated that genetic variants of the enzyme steroid 5
reductase type II (SRD5A2) are associated with serum
concentrations of major androgen metabolites such as
conjugates of androstane-3,17-diol-glucuronide
(3-diol-G). However, this association was not consis-
tently found among different ethnic groups. Thus, we
aimed to determine whether the association with
SRD5A2 genetic variations exists in a cohort of healthy
Chinese elderly men, by examining 2 metabolite con-
jugates: androstane-3,l7-diol-3-glucuronide (3-
diol-3G) and androstane-3,17-diol-17-glucuronide
(3-diol-17G).
METHODS: We used GC-MS and LC-MS to measure se-
rum sex steroid concentrations, including testoster-
one and dihydrotestosterone, and 3-diol-3G and
3-diol-17G in 1182 Chinese elderly men age 65
and older. Genotyping of the 3 SRD5A2 tagSNPs
[rs3731586, rs12470143, and rs523349 (V89L)] was
performed by using melting-temperature–shift
allele-specific PCR.
RESULTS: The well-described SRD5A2 missense variant
rs523349 (V89L) was modestly associated with the 3-
diol-17G concentration (P = 0.040). On the other
hand, SNP rs12470143 was found to be significantly
correlated with 3-diol-3G concentration (P = 0.021).
Results of haplotype analysis suggested that the pres-
ence of an A-C-G haplotype leads to an increased 3-
diol-3G concentration, a finding consistent with re-
sults of single SNP analysis.
CONCLUSIONS: The genetic variation of SRD5A2 is asso-
ciated with circulating 3-diol-3G and 3-diol-17G
concentrations in Chinese elderly men. In addition, we
showed that SRD5A2 haplotypic association, rather
than a single SNP alone, might be a better predictor of
the 3-diol-G concentration. Thus, the effect of either
the haplotype itself or of other ungenotyped SNPs in
linkage disequilibrium with the haplotype is responsi-
ble for the interindividual variation of 3-diol-G.
© 2010 American Association for Clinical Chemistry
Serum concentrations of sex steroids and metabolites
have been associated with human development (1) and
clinical diseases such as prostate cancer (2, 3 ). Thus,
there are important reasons to study as complex traits
the variations in circulating sex steroid concentrations
in individuals and across ethnic groups. In particular,
circulating sex steroid concentrations have been asso-
ciated with various genetic factors (4–7). For example,
testosterone has familial correlations and genetic de-
terminants (8), and estrogen also correlates with ge-
netic polymorphisms (7, 9, 10 ). Results of recent stud-
ies in twins showed a high heritability of plasma sex
hormone concentrations among adult male twins, with
heritability of 57% for testosterone (11, 12 ).
The latest explosion of genome-wide association
studies has enhanced our understanding not only of
genetic predisposition to various disease (as a qualita-
tive trait) (13 ) but also of the genetic determinants of
many quantitative traits (14 –16 ). Recently, Ahn et al.
(4) performed the first comprehensive association
study of genetic variation in the sex steroid metabolism
pathway. This investigation, which was a large-scale
study that included 5 groups of white men (n = 4720)
1
Departments of Chemical Pathology,
8
Medicine and Therapeutics, Faculty of
Medicine, and
9
Community and Family Medicine, Faculty of Medicine, and
5
School of Public Health and Primary Care and
6
Jockey Club Centre for
Osteoporosis Care and Control, Faculty of Medicine, The Chinese University of
Hong Kong, Hong Kong SAR, China;
2
Laboratory of Genetics of Disease
Susceptibility, Li Ka Shing Institute of Health Sciences, Hong Kong SAR, China;
3
Center for Bone Research at the Sahlgrenska Academy, Institute of Medicine
and
4
Center for Bone Research at the Sahlgrenska Academy, Departments of
Internal Medicine and Geriatrics, Gothenburg University, Gothenburg, Sweden;
7
Oregon Health and Science University, Portland, OR.
* Address correspondence to this author at: Department of Chemical Pathology,
Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales
Hospital, Shatin, New Territories, Hong Kong SAR, China. Fax +852-26365090;
e-mail nelsontang@cuhk.edu.hk.
Received May 28, 2010; accepted August 18, 2010.
Previously published online at DOI: 10.1373/clinchem.2010.150607
Clinical Chemistry 56:11
1742–1749 (2010)
Molecular Diagnostics and Genetics
1742
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