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Department of Chemical Pathology, St. Thomas’ Hospital (J.S., S.M., J.C., Y.T.M., A.S.W., M.W., G.N.H.), London, SE1 7EH United Kingdom; Osteoporosis Screening Unit, Guy’s Hospital (M.L.F., K.M.K., I.F.), London SE1 9RT United Kingdom; and Bone Research Group, Department of Medicine and Therapeutics, University of Aberdeen Medical School (S.H.R.), Aberdeen, AB25 2ZD United Kingdom
Address all correspondence and requests for reprints to: Geeta N. Hampson, M.D., Department of Chemical Pathology, 5th Floor, North Wing, St. Thomas’ Hospital, London, United Kingdom SE1 7 EH. E-mail: geeta.hampson{at}kcl.ac.uk.
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Abstract |
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-hydroxylase/17,20-lyase and aromatase, respectively, both involved in sex hormone synthesis. We investigated the association between 2 common polymorphisms in 1) the promoter region (T
C substitution) of CYP 17, and 2) exon 3 (GA) of CYP 19, bone mineral density (BMD) and serum androgen/estradiol, in a case-control study of 252 postmenopausal women aged 64.5 ± 9.2 yr (mean ± SD). There was no significant difference in serum estradiol concentrations between cases (n = 136) and controls (n = 116). The CYP 19 genotype was significantly associated with serum estradiol (P = 0.002). Women with the AA genotype had higher serum estradiol concentrations compared with those with the GG genotype (P = 0.03). In older women, those with the CYP 19 GA and GG genotypes had an increased prevalence of osteoporosis (P = 0.04) and fractures (P = 0.003). We found no significant association between CYP 17 genotype and serum androgens and estradiol concentrations. However, a significant association was seen between BMD values at the femoral neck with CYP 17 genotype in cases (P = 0.04) and in the whole study population (P = 0.012). Subjects with the CC genotype had significantly lower BMD (mean ± SD: TT, 0.7 ± 0.16; CC, 0.6 ± 0.08 g/cm2; P = 0.006). In conclusion, both CYP 17 and CYP 19 are candidate genes for osteoporosis in postmenopausal women. |
Introduction |
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Both androgens and estrogens are important for the development and maintenance of bone mass (5). The tissue or circulating levels of sex steroids are a function of their rates of production and removal. In postmenopausal women, peripheral or adrenal conversion of steroid precursors account for almost all of the circulating estrogens and testosterone concentrations (5). In addition, the adrenal cortex secretes dehydroepiandrosterone, dehydroepiandrosterone sulfate (DHEAS), and androstenedione. Although these adrenal androgens may have relatively weak effects on the skeleton, they are nevertheless an important source of substrate for the synthesis of more potent sex steroids (6). Therefore, the genes involved in the synthesis of androgens and estrogen are potential candidate genes for osteoporosis.
Cytochrome P450c17 (CYP17) encodes an enzyme with both 17-hydroxylase and 17,20-lyase activities, the rate-limiting step in androgen biosynthesis (7). 17-Hydroxylase is responsible for hydroxylating pregnelone and progesterone, which are then converted to C19 steroid precursors of testosterone and estrogen by 17,20-lyase activity. Loss of function mutations in the CYP 17 gene results in reduced growth and osteoporosis (8). A common polymorphic variant in the CYP17 gene (TC polymorphism situated 34 bp upstream from the translation initiation site) has been recently shown to be associated with femoral size and bioavailable testosterone concentrations in men (9). There have been no studies to date examining the possible effect of this polymorphism on BMD and sex steroid and adrenal androgen concentrations in postmenopausal women. Aromatase, an enzyme in the same biosynthetic pathway, plays a key role in the conversion of androgens to estrogens (10). It is the product of the CYP 19 gene, which is a member of the cytochrome P450 superfamily of genes. Aromatase is expressed in various tissues, including adipose, breast, and bone, where its activity influences local tissue concentrations of estrogens in a paracrine or intracrine fashion (11). Inactivating mutations of CYP19 are associated with increased bone turnover and decreased BMD (12). However, more subtle variations in aromatase activity, as a result of polymorphic variants, could affect the rate of synthesis of estrogens and thus contribute to osteoporosis. Indeed, a tetranucleotide simple tandem repeat polymorphism in intron 4 of the CYP19 gene has been related to both female and male osteoporosis (13). A silent polymorphism (GA at Val80) in exon 3 has been previously described and has been associated with breast cancer risk (14). However, there have been no studies to date investigating any association between this polymorphic variant and serum estradiol concentrations and BMD in postmenopausal women.
In the present study we tested the hypothesis that the CYP 17 and CYP 19 polymorphisms described above are associated with circulating sex steroid concentrations and BMD in a group of postmenopausal women.
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Subjects and Methods |
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Two hundred and fifty-two ambulant, community-dwelling, postmenopausal Caucasian women, between 46 and 80 yr of age, from southeast London, United Kingdom, agreed to take part in this case-control study. The study was approved by the local research ethical committee of Guy’s and St. Thomas’ Hospital National Health Service Trust, and all study participants gave informed consent. One hundred and thirty-six women with osteoporosis, defined by a T-score of -2.5 or less at the lumbar spine and/or hip sites, using the NHANES 111 study reference range, were recruited consecutively during their attendance at the metabolic bone clinic or the osteoporosis screening unit at Guy’s Hospital between May 2001 and October 2001. Individuals with secondary causes of osteoporosis or bone loss, such as inflammatory diseases, e.g. rheumatoid arthritis, malignancy, chronic renal failure, immobilization, hyperparathyroidism, thyrotoxicosis, and corticosteroid use, were excluded. Letters were sent to 150 local postmenopausal women who had previously had a dual energy x-ray absorptiometry (DXA) scan in the osteoporosis screening unit and had been found to have normal bone mineral density (BMD), inviting them to participate in the study. One hundred and forty-five of these women agreed. However, only 116 attended the osteoporosis screening unit for their appointment. For all study subjects, clinical information, such as age at menarche and menopause, years since menopause, history of fractures, intake of dairy products, alcohol intake, smoking habits, degree of exercise, and family history of osteoporosis, were obtained through a questionnaire. The characteristics of the study population are summarized in Table 1
. One hundred and eleven women (44%) had previously sustained a low trauma fracture. Types of fracture included vertebral (n = 19) and peripheral fractures, including wrist, hip, and humerus (n = 92). Only 3 patients had sustained a hip fracture. The majority of fractures in the control group were wrist fractures (n = 15). The prevalence of fractures in the control group (19%) was similar to the recent findings reported in 649 community-dwelling women, aged 65–85 yr, from the United Kingdom British doctors study register in Oxford and from a general practice in Ipswich, United Kingdom (15). After obtaining written consent, blood was obtained from all study participants for DNA extraction and for the measurement of sex steroids. For the hormone determinations, blood was centrifuged, and the serum samples were stored at -20 C until analysis.
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BMD at the lumbar spine (L1–L4), femoral neck, and total hip was measured by DXA (QDR-4500, Hologic, Waltham, MA). The coefficients of variation (CVs) for the in vivo BMD measurements were 1% (spine), 2% (femoral neck), and 1% (total hip). Baseline BMD values were used in the subjects with osteoporosis recruited at the metabolic bone clinic, before institution of antiresorptive therapy.
DNA extraction and analysis
Genomic DNA was extracted from peripheral blood leukocytes according to the manufacturer’s instructions using a kit (Nucleon genomic DNA extraction kit, Nucleon Biosciences, Tepmel Life Sciences PLC, Manchester, UK).
A 459-bp fragment of genomic DNA containing the T to C substitution at -34 bp in the CYP 17 gene was amplified by PCR as previously described (9). Primer sequences were as follows: forward, 5'-CATTCGCACTCTGGAGTC-3'; and reverse, 5'-AGGCTCTTGGGGTACTTG-3'. The T to C polymorphism creates a recognition site for the restriction enzyme MspA1. After amplification, all samples were digested overnight with 5 U MspA1. In subjects with the C allele, two smaller fragments of 335 and 124 bp were obtained, as shown in Fig. 1A. For determination of the GA polymorphism at position Val80 in CYP 19, a 188-bp PCR product was generated. The PCR was carried out in a 25-µl reaction mixture containing 200 ng genomic DNA, 2.0 mM magnesium chloride, 250 µM deoxy-NTPs, 0.5 µM of each primer, and 0.5 U Taq DNA polymerase. Primer sequences were as follows: forward, 5'-AGTAACACAGAACAGTTGCA-3'; reverse, 5'-TCCAGACTCGCATGAATTCTCCGTA-3'. A mismatch (G instead of A) was introduced in the reverse primer to create a restriction site for the enzyme Rsa1. The presence of the G variant in CYP19 resulted in digestion of the 188-bp amplicon to two smaller fragments of 164 and 24 bp. The fragments were separated on a 3% agarose gel containing ethidium bromide and viewed by UV illumination. A representative experiment showing the different genotypes is shown in Fig. 1B. Only one 188-bp fragment was seen in subjects with the AA genotype. In subjects with the GA genotype, two bands of 188 and 164 bp were seen, whereas in those subjects homozygous for the G variant (GG), only one 164-bp PCR fragment is seen. All PCR amplifications were carried out using a DNA thermocycler (Gene Amp PCR system 9700, PE Applied Biosystems, Foster City, CA). After an initial denaturation at 95 C for 5 min, 35 cycles of amplification with denaturation at 95 C for 30 sec, annealing at 56 C for 30 sec, and extension at 72 C for 30 sec were performed, followed by a final extension step of 7 min at 72 C. The PCR product was digested overnight with 5 U Rsa1. In samples where the genotype was ambiguous, the PCR reaction was repeated, and the genotype verified again. Control samples with known genotypes were also run to check on the reproducibility of the digestion step.
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Serum testosterone and DHEAS were measured on the Centaur (Bayer plc, Newbury, UK) and Immulite (Immulite, Glyn Rhonwy, UK) analyzers, respectively. The reference range for total testosterone concentrations for women is 14.4–75 ng/dl (0.5–2.6 nmol/liter). Intra- and interassay CVs were 2.3–6.2% and 1.4–4.7%, respectively. Free testosterone concentrations were derived using the following formula: [6.11–2.38 (log10 SHBG)] x 10 total testosterone. The age-related reference ranges for serum DHEAS were as follows: 20–40 yr, 0.65–4.4 µg/ml (1.7–11.5 µmol/liter); 40–60, 0.3–2.6 µg/ml (0.8–6.9 µmol/liter); and more than 60 yr, 0.15–1.8 µg/ml (0.4–4.7 µmol/liter). Intra- and interassay CVs were 6.8–9.5% and 8.1–15%, respectively. Androstenedione was measured by RIA using a commercial kit (Ortho-Clinical Diagnostics, Amersham, UK). The reference range for women is 14.3–74.5 ng/dl (0.5–2.6 nmol/liter), with intra-and interassay CVs of 2.3–6.2% and 1.4–4.7%, respectively. Serum estradiol was measured by RIA using the ESTR-US-CT kit (CIS Bio International, Gif-Sur Yvette, France). The reference range for postmenopausal women is 3–13.5 pg/ml (11–50 pmol/liter). Intra- and interassay CVs were 4.5% and 6.5%, respectively. The detection limit of the assay was 1.6 pg/ml (6.0 pmol/liter), and the assay CV at this concentration was 10.6%.
Statistical analysis
An allele dose-effect model with linear regression analysis was used throughout. Hardy-Weinberg equilibrium was tested using the standard 
2 test comparing the expected and actual allele frequencies. ANOVA was used to identify any potential association between phenotypes and genotypes. Stepwise multiple regression with backward elimination was performed with BMD and log-transformed sex hormone concentrations as dependent variables, entering age, body mass index (BMI), menopausal age, age at menarche, years since menopause, dietary calcium intake, tobacco and alcohol use, and level of daily exercise as independent variables. A 2 test was used to compare fracture prevalence between genotypes. A t test was used when two groups were compared. Partial coefficients of determination (r2) were used to estimate the independent contribution of the CYP 17 and CYP 19 polymorphisms to the total variance in BMD and log-transformed sex hormone concentrations. Statistical analyses were performed using GB stat version 6 (Dynamic Microsystems, Inc., Silver Spring, MD).
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Results |
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and B. All distributions were in Hardy-Weinberg equilibrium. There was no significant difference in genotype frequency between cases and controls for CYP 19 (P = 0.23). However, the CYP 17 CC genotype was overrepresented in cases compared with controls, as shown in Table 2A, although the results failed to reach statistical significance (P = 0.08). There was also a trend toward lower BMD values at the femoral neck in cases and controls in subjects with the CC genotype (P = 0.08). When combining both groups, we observed a significant difference in femoral neck and total hip BMD between subjects with the different CYP 17 genotypes. Individuals with the CC genotype had significantly lower BMD at the hip sites compared with those with the TT and TC genotypes. This was still significant when using the z-scores, as women with the TC genotype were significantly older than women with the CC genotype (z-scores, mean ± SD: TT, -0.082 ± 1.07; TC, -0.291 ± 1.03; CC, -0.59 ± 0.78; P = 0.043. TT vs. CC) and after adjustment for factors such as age, height, weight, level of exercise, and dairy intake (Table 2A). A significant trend in BMD differences at the femoral neck by CYP 17 genotype was found using linear regression analysis (P = 0.032). There was a significant trend toward an increase in fracture prevalence in subjects with the CC genotype (P = 0.0436; Fig. 2). In a multiple linear regression model, we found that the CYP 17 polymorphism was a significant independent predictor of BMD at the femoral neck in cases (P = 0. 04), with a weaker association in controls (P = 0.15). However, when combining the two groups, the association became stronger (P = 0.0128) due to the increase in power (Table 3). No association was observed with CYP 19 in the whole study population, and there was no significant difference BMD between the CYP 19 genotypes.
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, A and B. We observed a significant difference in serum estradiol concentrations only between the CYP 19 genotypes (Table 4B). Subjects with the GG genotype had significantly lower estradiol concentrations, as shown in Table 4B. In a multiple regression model in the combined study population with natural logarithm (LN) and with estradiol concentrations as the dependent variable, weight, height, and CYP 19 genotype were the only significant predictors of serum estradiol concentrations (Table 5). The significant association between serum estradiol concentrations and the CYP 19 genotype was also present when analyses were carried in cases only (P = 0.0085). In multiple regression analyses with log-transformed serum androgens (testosterone, bioavailable testosterone, DHEAS, androstenedione) as dependent variables, BMI appeared to be the only significant independent predictor.
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10 yr since the menopause; n = 182; mean ± SD age, 68 ± 7.5). In this subgroup, subjects with the AA genotype had significantly higher z-scores at the hip compared with the GG or GA genotype [z-scores (mean ± SD): AA (n = 44), 0.15 ± 1.19; GG (n = 39), -0.29 ± 0.82; GA (n = 95), -0.28 ± 1.19; P = 0.05, AA vs. GA; P = 0.04 AA vs. GG]. However, after adjustment for confounding factors such as BMI, level of physical activity and BMD at the hip and femoral neck were not significantly different among the three genotypes. There was a significant overrepresentation of osteoporosis and fractures in this older subgroup in subjects with the GA and GG genotypes compared with those with the AA genotype (Fig. 3).
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Discussion |
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In contrast to Zmuda et al. (9), who found an increase of 20% in bioavailable testosterone levels in men with the CYP 17 CC genotype, we observed no significant difference between CYP 17 genotypes and circulating sex hormone concentrations in women. Indeed, studies in women with breast and endometrial cancer have failed to consistently find an association between the CYP 17 polymorphism and serum levels of androgens and estradiol (17, 18). In women, as serum concentrations of testosterone are significantly lower than in men, it may be more difficult to detect the relatively small effect of the CYP 17 polymorphism. However, surprisingly, although we found no association between the androgenic precursors and the CYP 17 polymorphism, we found a lower BMD at the femoral neck in the whole study population in those women with the CC genotype. A similar trend was found in cases and controls separately, although the results failed to reach statistical significance due to the relatively small numbers. As testosterone has more important effects on the maintenance of skeletal integrity and bone size in men, the CYP 17 polymorphism may play a more significant role in the androgen synthetic pathway in males. In contrast, in women, the functional effect of the CYP 17 polymorphism may be via its influence on the glucocorticoid synthetic pathway (7). It is now established that glucocorticoids can have negative effects on bone formation by increasing osteoblastic apoptosis (22). The CYP 17 polymorphism may thus have a gender-specific effect on bone metabolism. Indeed, we found a significant association between BMD at the femoral neck and the CYP 17 polymorphism in cases and the whole study population over and above environmental factors such as age, calcium intake, and exercise with lower BMD in the CC genotype as discussed above. Our findings are in contrast to those of Zmuda et al. (9), who observed an increase in femoral size in men with the CC genotype, although they failed to see any difference in femoral neck BMD. The lack of an effect at the spine observed in our study may be explained at least in part by the limitations of DXA measurements at this site in the older population due to osteoarthritic/degenerative changes, although spinal radiographs were not performed in our study population to exclude those changes (23). Secondly, although there is evidence to suggest that genetic factors play an important role in the regulation of both spine and hip BMD, linkage-based studies in both man and experimental animals have shown that the quantitative trait loci for regulation of spine BMD and hip BMD are, for the most part, nonoverlapping (24, 25). This could indicate that genes that regulate BMD at these two sites are probably different.
The present study shows a significant association between the CYP 19 polymorphism and serum estradiol concentrations in the whole study population and in cases. Our findings that the CYP 19 polymorphism described in this study may be associated with the maintenance of tissue estrogen levels are consistent with the findings of overrepresentation of the AA genotype in breast cancer patients (14). Our data also confirm the findings of previous studies in other patient populations with, for example, prostate cancer, where significant associations between CYP 19 polymorphisms and circulating estradiol concentrations were found (21). No significant association was seen between BMD and the CYP 19 polymorphism in the whole study population. This is in contrast to the findings by Masi et al. (13) of a significant association between vertebral BMD and the number of (TTTA) repeats in intron 4 of the CYP 19 gene, an effect that they showed to be more pronounced within 5 yr of the menopause. However, in this study the GA and GG genotypes were associated with an increased prevalence of osteoporosis and fractures in older women. Our findings are biologically plausible, as the contribution of this polymorphic variant to disease is related to its effect on long-term estrogen exposure and therefore may become more apparent in older populations. As the current study was explorative and hypothesis generating, further studies with larger study populations are needed to confirm this.
The molecular mechanisms by which the CYP 17 and CYP 19 polymorphisms are associated with femoral neck BMD and serum estradiol, respectively, are unclear. CYP 17 is relatively small, approximately 7 kb in size. Several single nucleotide polymorphisms (SNPs) have been described in CYP 17. However, apart from the T to C polymorphism, only three SNPs have been validated by frequency (rs 6162, rs 6163, and rs 6164). Two of these (rs 6162 and rs 6163) are very close and are situated at the 5' end of the gene. These two SNPs are likely to be in strong linkage disequilibrium with each other and with the T to C polymorphism, which is in the promoter region of CYP 17. The third SNP (rs 6164) is located at the 3' end of CYP 17. However, given the small size of the gene, this SNP too may be in linkage disequilibrium with the T to C polymorphic variant, although this merits further investigations. It has been postulated that the T to C substitution in CYP 17 creates an additional SP 1-type (CCACC box) promoter site that may lead to increased expression of the gene. It is therefore likely that the C polymorphic variant could lead to increased enzyme expression, resulting in increased 17-hydroxylase activity and glucocorticoid synthesis, although data are conflicting (26). Further studies are required to confirm this. Similarly, for the CYP 19 polymorphic variant described in the present study, it is not known whether or how this genetic variation affects aromatase activity. This polymorphism may be in linkage disequilibrium with other polymorphic sites in CYP 19. Indeed, it has been shown to be in linkage disequilibrium with the (TTTA)7 allele, which is itself in strong linkage disequilibrium with a C/T base change in exon 10 of CYP 19 (14, 27, 28). This latter substitution has been shown to influence aromatase mRNA levels and to be associated with alternative promoter use. It remains to be further investigated whether the polymorphic variant described in this study has a direct functional effect through possible changes in mRNA stability, the creation of a splice site, a promoter effect, or alterations in the enzyme’s sensitivity to aromatase inhibitors (29).
In summary, our data suggest that the TC polymorphism in CYP 17 is significantly associated with femoral neck BMD in postmenopausal women in the United Kingdom, although further confirmatory studies are required. The CYP 19 GA polymorphism is significantly related to estradiol concentrations, and its effects on the prevalence of osteoporosis and fracture rate in older women may be attributable to its influence on estradiol synthesis. The CYP 19 genotype may thus provide a useful marker in postmenopausal women of long-term tissue estrogen exposure and disorders in which estrogen is implicated. In conclusion, both CYP 17 and CYP 19 are candidate genes involved in the maintenance of bone mass and may contribute to the complex pathogenesis of osteoporosis.
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Footnotes |
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Received January 31, 2003.
Accepted October 3, 2003.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-hydroxylase/17,20-lyase deficiency: from clinical investigation to molecular definition. Endocr Rev 12:91–108[Medline]
(CYP17) gene is associated with bioavailable testosterone levels and bone size in men. J Bone Miner Res 16:911–917[CrossRef][Medline]
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