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From the * Endocrinology Division, Central Drug
Research Institute, Lucknow, India; the Centre
for Cellular and Molecular Biology, Uppal Road, Hyderabad, India, and the
Departments of Human Genetics and
Urology, Sri Ramachandra Medical College and
Research Institute (Deemed University), Porur, Chennai, India.
| Correspondence to: K Thangaraj, Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500 007, India (e-mail: thangs{at}ccmb.res.in). |
| Received for publication December 15, 2008; accepted for publication May 13, 2009. |
Testosterone is converted to 5
-dihydrotestosterone (DHT) by 5
-reductase enzyme, which is encoded by the SRD5A2 gene. DHT is
the main androgen responsible for prostate growth. We have analyzed the
complete coding region of the SRD5A2 gene in 87 histologically
confirmed prostate cancer (PC) patients, 40 benign prostatic hyperplasia (BPH)
cases, and 96 control samples from southern parts of India. The study revealed
the A49T site to be monomorphic, the V89L site to be highly polymorphic, and
the (TA)n repeat site to be polymorphic with only 2
alleles in our populations. The distribution of V89L alleles between PC cases
and controls was not significantly different; however, (TA)9
alleles distributed differently between the 2 groups. BPH cases exhibited
alleles similar to controls at all polymorphic sites. The sequencing of the
whole coding region did not reveal any other known or novel polymorphism in
this gene. Our study emphasizes that the (TA)9 allele might confer
certain PC risk but that A49T and V89L polymorphisms do not confer PC risk in
South Indian men.
Key words: South Indian population, 5 reductase, testosterone, dihydrotestosterone, benign prostatic hyperplasia
-dihydrotestosterone) are actively
involved in prostate development (Heinlein
and Chang, 2004). Approximately 80%–90% of prostate cancers
are dependent on androgens at initial diagnosis, and endocrine therapy of PC
is directed toward the reduction of serum androgens and inhibition of androgen
receptor (AR) (van der Kwast et al,
1991). Therefore, the AR gene has been studied
extensively in PC, and polymorphisms in the AR gene have been
associated with PC risk (for review see
Rajender et al, 2007).
Testosterone, after entering into the target cells, is converted to the
more potent androgen dihydrotestosterone (DHT) by the action of the enzyme, 5
-reductase (Wilbert et al,
1983; Coffey,
1993). DHT is mainly responsible for prostate growth, and it has
been demonstrated that the tissue DHT level is a useful marker in predicting
the clinical response of prostate cancer to anti-androgen therapy
(Geller et al, 1984). The
levels of DHT and resulting androgen action vary among different individuals
depending on the activity of 5 -reductase. Ross et al
(1992) demonstrated that young
Japanese men have lower 5 -reductase activity than young Caucasian
American and African American men. Similarly, Wu et al
(1995) reported that the
DHT:testosterone ratio was highest in African Americans, intermediate in
Caucasians, and lowest in Asian Americans, corresponding to the respective
risk of developing PC in these groups. Taking the above into consideration, it
has been hypothesized in several studies that the polymorphisms in the
SRD5A2 gene could affect PC risk
(Kantoff et al, 1997;
Lunn et al, 1999;
Hsing et al, 2001;
Latil et al, 2001).
The human SRD5A2 gene, mapped on chromosome 2 (2p23), has 5 exons
and 4 introns and encodes the enzyme 5 -reductase, expressed in
androgen-dependent tissues (Thigpen et al,
1993). A number of mutations/polymorphisms have been identified in
the SRD5A2 gene; however, A49T, V89L, and (TA)n
repeat polymorphisms are the most frequent. Most of the study till date have
analyzed only A49T, V89L single-nucleotide polymorphisms, and
(TA)n polymorphic repeat regions. Controversies exist
regarding the association of these polymorphisms with PC risk
(Ntais et al, 2003). The
meta-analyses are of immense use in such situations to resolve controversies;
however, the bias in the publication of the studies showing positive
correlation rather than no correlation might make the meta-analysis less
transparent. To assess the correlation more judiciously, the studies finding
no significant correlation of the polymorphism(s) with the disorder should
also be brought forward, and an effort should be made to generate data on
various populations of the world. This study is such an effort. We analyzed
the SRD5A2 gene for mutations/polymorphisms in Indian PC patients. To
the best of our knowledge, no previous study has analyzed the full coding
region of the SRD5A2 gene among Indian prostate cancer patients. We
have undertaken sequencing of the full coding region and a part of the
3' UTR region encompassing the (TA)n repeat of the
SRD5A2 gene to understand the role of SRD5A2 polymorphisms
in disease risk and to assess the racial and ethnic differences from other
populations of the world (Table
1).
|
Materials and Methods
Subjects
The study included 87 histologically confirmed PC cases, 40 BPH patients,
and 96 male control subjects from the southern parts of India. The control
comprised healthy individuals with normal serum PSA levels of 4 ng/mL of blood
or less (reference level, <4 ng/mL), with no previous history of cancer,
which was confirmed by digital rectal examination. BPH patients had normal
serum PSA levels (
4 ng/mL) and were examined by digital rectal examination
to confirm enlarged prostate. However, no histology could be done for the BPH
group because of the lack of biopsy. All cases and controls were enrolled
under informed written consent. The patients and controls were enrolled from a
population with the same ethnic origin. Relevant clinical and pathological
data were collected for all the patients. In PC patients age ranged from 45 to
98 years, with a mean age of 67.5 years; 55–77 years with a mean of 65.5
years in BPH patients, and 50–81 years with a mean of 66.5 years in
normal healthy controls. Pathological grading of the tumors by Gleason scores
was obtained, and the patients were classified as low grade if their Gleason
scores were less than 7 and high grade if their Gleason scores were greater
than or equal to 7. The Gleason score was less than 7 in 48 patients and
greater than or equal to 7 in 39 patients. The study was approved by the
ethical committee of the Institute.
Genetic Analysis of SRD5A2 Gene
Genomic DNA was isolated from peripheral blood lymphocytes by the method
described in our earlier study (Thangaraj
et al, 2002). The primers used for polymerase chain reaction (PCR)
amplification of the SRD5A2 gene, including intron/exon junctions,
were designed with GeneTool software and synthesized with the use of a 394
DNA/RNA oligosynthesizer (Applied Biosystems, Foster City, California).
Conditions for PCR amplification along with primer sequences for each exon are
detailed in Table 2. The PCR
products were sequenced directly by the dideoxy cycle sequencing chain
termination method (Big Dye V3.1, Applied Biosystems) on an ABI 3730 DNA
analyzer (Thangaraj et al,
2003). Sequence editing and multiple alignments were carried out
with AutoAssembler software (Applied Biosystems). The sequencing signal for
the V89L polymorphism was not clear at the polymorphic site despite repeated
efforts; therefore, this polymorphism was typed by PCR restriction fragment
length polymorphism (PCR-RFLP). The restriction reaction included a 10-µL
PCR product, 2 units of RsaI restriction enzyme, 10 µL of
restriction buffer, and incubation at 37°C for 1 hour. After restriction
digestion, the reaction mixture was run on 10% PAGE to see the banding
pattern. For distinguishing the homozygous and heterozygous genotypes at the
(TA)9 repeat, we amplified this region with the FAM
(carboxyfluorescein)-labeled forward primer
(Table 2) and genotyped it with
3730 DNA analyzer. For genotyping, 3.0 µL of PCR product was mixed with 0.3
µL of LIZ size standard (Applied Biosystems) and 6.7 µL of Hi-Di
formamide (Applied Biosystems). Before running on the DNA analyzer, the
mixture was heated to 95°C for 5 minutes, followed by cooling on ice for 5
minutes.
|
Statistical Analyses
We calculated the allelic percentages for SRD5A2 polymorphisms and
analyzed them for differences between cases and controls. Because it is known
that the SRD5A2 allele with valine (Val) at the V89L polymorphic site
confers high activity to the enzyme compared with the allele with leucine
(Leu) (Makridakis et al,
2000), the genotypes at this site were named high-activity
(Val/Val) and low-activity (Val/Leu and Leu/Leu) genotypes. The high- and
low-activity genotypes were analyzed for differences between cases and
controls. The test was performed for PC vs controls and BPH vs controls,
independently. We used the chi-square (
2) test to calculate
the significance of differences between cases and controls. Chi-square values
were calculated with the online Vassar Stats Calculator
(http://faculty.vassar.edu/lowry/VassarStats.html).
Two-sided P values of less than .05 were taken to be significant. We
analyzed the frequency distribution of various genotypes at the V89L
polymorphic site with respect to various clinical parameters using SPSS
software (version 11; SPSS Inc, Chicago, Illinois). Furthermore, different
alleles at the V89L and (TA)n polymorphic sites were
examined for linkage disequilibrium in both the cases and the controls.
Results
We did not observe any polymorphism at the A49T polymorphic site (Table 3). PC, BPH, and control samples invariably had the wild-type allele (A) at this site. The V89L site was highly polymorphic (Figure 1); however, the differences in the frequency distribution of various alleles/genotypes at this site were not significant between PC cases and controls or BPH and controls (Table 3). For genotype analyses, the Val/Val genotype was considered to be a high-activity genotype, whereas Val/Leu and Leu/Leu were considered to be low-activity genotypes. We did not find any difference between cases and controls in the distribution of high- and low-activity genotypes (Table 4). At the (TA)n repeat site, we observed the (TA)0 allele to be the most common in both the cases (97.7%) and the controls (100%), whereas (TA)9 occurred at a very low frequency (2.3%) among the PC cases only (Table 3). PC cases exhibited all 3 possible genotypes at the (TA)n site, with a maximum frequency (96.55%) of (TA)0/(TA)0, a low frequency (2.3%) of (TA)0/(TA)9, and an even lower frequency (1.15%) of (TA)9/(TA)9 (Table 4). BPH and control samples invariably presented with the (TA)0/(TA)0 genotype, with the other 2 genotypes being absent. Although the genotypes with longer (TA)n alleles were not so common in the cases, its absence from the control and BPH groups might indicate disease risk associated with longer alleles in a subpopulation of Indian men. Haplotype analyses indicated that the presence of the (TA)9 repeat did not preferentially associate with Val/Val, Val/Leu, or Leu/Leu genotypes at the V89L site, indicating the absence of linkage disequilibrium between the 2 polymorphic sites. Correlation analyses showed that the presence of the Val/Leu and Leu/Leu genotypes at this site correlated with higher levels of PSA compared with the Val/Val genotype (r = .301, P = .005; Figure 2). No other parameter correlated positively or negatively with the V89L polymorphic site. BPH cases possessed alleles and genotypes similar to the control samples at all the 3 polymorphic sites.
|
|
|
|
Discussion
Testosterone and its metabolite DHT are crucial for growth and development of prostate gland. The research on PC has focused mainly on the genes related to androgen action. In this study, we have sequenced the entire coding region and 3' UTR region encompassing the (TA)n repeat of the SRD5A2 gene in 87 PC cases, 40 BPH cases, and 96 control samples. Most of the studies on the SRD5A2 gene in PC have focused only on these 3 polymorphisms (A49T, V89L, and [TA]n repeat). We have for the first time analyzed the entire coding sequence. The study revealed no polymorphism at the A49T locus. Differences in the distribution of (TA)n alleles but not V89L alleles were observed between the cases and the controls. Earlier studies on these polymorphisms in SRD5A2 have shown contradictory results. However, a meta-analysis has shown no significant association of any of these polymorphisms with prostate cancer susceptibility (Ntais et al, 2003). More studies might help to resolve the controversy regarding the association of genetic variations in the SRD5A2 gene with PC risk.
We observed no polymorphism at the A49T locus. All PC, BPH, and control
samples had A at this site. A49T has been one of the most commonly studied
polymorphisms in the SRD5A2 gene. The A49T variant (Ala 49 Thr
substitution) has been linked to pathological characteristics of PC
(Jaffe et al, 2000). It
increases the activity of the steroid 5--reductase enzyme by 5-fold.
The T variant has been found to be more prevalent in Caucasians (3.5%) than
African Americans, Asians, or Hispanics
(Jaffe et al, 2000). An A49T
amino acid substitution increased the risk of clinically significant disease
by 7.2-fold in African American men (95% confidence interval [CI],
2.17–27.91; P = .001) and 3.6-fold in Hispanic men (CI,
1.09–12.27; P = .04). The polymorphism was reported to increase
PC risk, and the mutant enzyme had a higher in vitro Vmax
than the normal enzyme (9.9 compared with 1.9 nmol - min–1
mg–1; Makridakis et al,
1999). This polymorphism has been reported among Caucasian men and
Asians but showed no association with PC risk
(Latil et al, 2001;
Mononen et al, 2001;
Soderstrom et al, 2002).
Earlier studies on Japanese (Yamada et al,
2001) and Chinese men (Hsing et
al, 2001) also demonstrated monomorphism at the A49T locus. Taking
our results into account, it appears that Asian or, more narrowly, South
Asians have similar alleles (A) at this locus, which might signify their
genetic affinities. Indian men thus carry a low-risk allele at this locus
compared with Caucasians, African Americans, and Hispanics. Nevertheless, it
is very important to generate similar data for other Indian and South Asian
populations to strengthen or refute the above statement.
We observed the V89L site to be highly polymorphic, but no significant
difference was observed between PC cases and controls or BPH and control
samples. The V89L substitution occurs at a frequency of 8.5% in Caucasians,
2.5% in African Americans, and 28% in Taiwanese men
(Nwosu et al, 2001). The V89L
polymorphism is more common than the A49T, at around 30% frequency
(Febbo et al, 1999;
Jaffe et al, 2000;
Makridakis et al, 2000). It
has been shown that the distribution of V89L genotypes parallels the
patterns of PC incidence in high- and low-risk populations, with an Leu/Leu
genotype prevalence of 22%–25% among Asians and of only about 4% among
Caucasian and African Americans, and a Val/Val genotype prevalence of
27%–29% among Asians and about 58% among African and Caucasian Americans
(Makridakis et al, 1999;
Ross et al, 1992;
Yamada et al, 2001).
Similarly, Nam et al (2001)
have claimed a 3.3-fold increased risk of disease recurrence with the Val/Val
and Val/Leu genotypes in Canadian populations. The results of the above
studies are supported by in vitro studies showing that, compared with the
Val/Val genotype, the Leu/Leu genotype confers a 42% reduction in 5
-reductase enzymatic activity
(Makridakis et al, 2000).
Conversely, other studies on French
(Cussenot et al, 2007) and
Swedish populations (Giwercman et al,
2005) reported that the Leu/Leu genotype is associated with PC
risk. This polymorphism has not found significant association with PC risk
among Caucasian men (Febbo et al,
1999; Lunn et al,
1999) and in Japanese men
(Yamada et al, 2001). Similar
to the above studies, we did not observe any difference in the distribution of
V89L alleles/genotypes between cases and controls. An earlier study of a North
Indian population also reported no association of the V89L polymorphism with
PC risk (Sobti et al, 2006).
In all the studies on South Asian populations, no association was detected
with the V89L polymorphism; however, contradicting results are evident from
studies on other populations (Table
1).
The (TA)n repeat site has been relatively less studied. Since identification of the (TA)n repeat polymorphism, 3 major alleles have been reported—(TA)0, (TA)9, and (TA)18—with (TA)0 being the most common in most of the populations (Akalu et al, 1999). The observation that the rare (TA)18 allele is limited to African American populations (Reichardt et al, 1995), who have a higher rate of prostate cancer than Asian American or Caucasian men (Parkin et al, 1997), suggests that a longer allele might be associated with increased enzyme activity. The relevance of the (TA)n marker in prostate cancer is further supported by the finding that 56% of 30 prostate tumors possessed somatic mutations at this locus (Akalu et al, 1999). Thus, polymorphism at this locus might increase the risk of prostate cancer. We observed the (TA)9 allele in 2.3% of the cases, although the frequency was too low to lay a strong association with PC risk (Table 3). In contrast, certain case control studies in Caucasian and Asian men have not found the (TA)9 variant to be associated with an increased prostate cancer risk (Kantoff et al, 1997; Hsing et al, 2001; Latil et al, 2001). In a few other studies, the longer (TA)n was not found to be associated with increased prostate cancer risk (Kantoff et al, 1997; Hsing et al, 2001; Latil et al, 2001). The longest allele, (TA)18, was found exclusively in African Americans, who are at increased risk of prostate cancer (Reichardt et al, 1995). In accordance with the above observation, the (TA)18 allele was absent from our cases as well controls.
A49T and V89L polymorphisms are present in the coding regions of the
SRD5A2 gene and hence affect the enzyme activity by amino acid
substitutions. But the (TA)n repeat is located in the
3' UTR of the SRD5A2 gene; therefore, it is unlikely to affect
the structure or function of the resulting protein. However, it has been
proposed that this polymorphism might influence regulation of 5
-reductase enzyme production
(Reichardt et al, 1995;
Kantoff et al, 1997), probably
by altering mRNA stability (Zubiaga et al,
1995). As a result, this polymorphism might alter DHT levels and
consequently the risk of developing PC
(Reichardt et al, 1995).
However, currently no study has addressed length of the
(TA)n repeat in concert with intraprostatic levels of DHT.
Out of 14 studies listed in Table
1, only 5 (35.71%) have analyzed the A49T polymorphism, 12
(85.71%) have analyzed the V89L polymorphism, and only 3 (21.43%) have
analyzed the (TA)n repeat. Only 2 studies (14.28%) have
analyzed all 3 polymorphisms discussed above. Contrasting results for the A49T
and V89L polymorphisms in our populations and the PC risk associated with
longer (TA)n alleles emphasize the need to analyze the
(TA)n repeat polymorphism in addition to A49T and V89L
polymorphisms in further studies on this gene. Nevertheless, no study to date
has analyzed the effect of the environment, if any.
Our study revealed monomorphism at the A49T locus and polymorphisms at the V89L and (TA)n sites. Inference on the basis of other populations indicates that our population carries a low-risk allele at the A49T site. Different variants at the V89L locus were almost equally frequent and conferred no PC risk. We found that the presence of the (TA)9 allele might confer a PC risk; however, the difference was small. As observed in other populations, the (TA)18 allele was absent from our samples, which could be for ethnic reasons. Sequence analysis of the whole coding region of the SRD5A2 gene did not reveal any other known or novel polymorphism. Therefore, it seems that V89L and (TA)n are the major polymorphic sites in the SRD5A2 gene in our population. The allelic variations in BPH were similar to controls at the (TA)n site, but the absence of longer (TA)n alleles in BPH cases cannot be ascertained given the lesser number of these cases in this study. The limitation of the sample size and certain variations in the percentage of various alleles on increasing the sample size cannot be denied. Our study emphasizes that A49T and V89L are not useful markers to use to estimate PC risk in Indian men, but the (TA)9 repeat might be associated with PC risk to a certain extent; however, the low frequency limits any diagnostic value of this polymorphism. Therefore, it is clear from our study that the polymorphic status of the SRD5A2 gene is entirely different in Indian populations. We strongly suggest analysis of the SRD5A2 gene in more populations to clearly understand the conflicting observations regarding the association of A49T, V89L, and the (TA)n repeat polymorphisms with PC risk.
Acknowledgments
We are thankful to all the patients and control individuals for kind participation in the study.
Footnotes
Supported by CSIR and ICMR, New Delhi, Government of India.
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