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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-0864
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 1 307-312
Copyright © 2006 by The Endocrine Society

Nuclear Receptor Coactivator-3 Alleles Are Associated with Serum Bioavailable Testosterone, Insulin-Like Growth Factor-1, and Vertebral Bone Mass in Men

Yah-Tyng Sheu, Joseph M. Zmuda, Jane A. Cauley, Susan P. Moffett, Clifford J. Rosen, Chandra Ishwad and Robert E. Ferrell

Departments of Epidemiology (Y.-T.S., J.M.Z., J.A.C., S.P.M.) and Human Genetics (C.I., R.E.F.), Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15261; and Maine Center for Osteoporosis Research and Education (C.J.R.), St. Joseph Hospital, Bangor, Maine 04401

Address all correspondence and requests for reprints to: Joseph M. Zmuda, Ph.D., Graduate School of Public Health, University of Pittsburgh, 130 DeSoto Street, Pittsburgh, Pennsylvania 15261. E-mail: zmudaj{at}edc.pitt.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Nuclear receptor coactivator-3 (NCOA3) is a member of the steroid receptor coactivator family that interacts with nuclear hormone receptors to enhance their transcriptional activation function and may play a role in somatic growth.

Objective: The aim of this study was to examine the relationships between the CAG/CAA (glutamine) length variation at the NCOA3 locus, sex steroid hormone, and IGF-I levels and bone mineral density (BMD) in a cohort of older Caucasian men.

Design and Methods: We analyzed the association between potentially functional alleles at this locus, serum sex steroid hormone, and IGF-I levels and lumbar spine and proximal femur BMD (Hologic QDR) in 263 community-dwelling Caucasian men (age 66 ± 7 yr, mean ± SD; range 51–84 yr). Men were genotyped for a CAG/CAA repeat polymorphism in NCOA3, which encodes a polyglutamine tract of variable length in the C-terminal transcriptional activation domain of the protein.

Results: We found a significant monotonic decrease in lumbar spine, but not hip, BMD with increasing copies of the most common allele (29 repeats, 53%). For example, men with the 29/29 genotype had 6% or nearly 0.5 SD lower spine BMD than men without this genotype, and NCOA3 genotype explained 3.2% of the phenotypic variation in this trait. Serum levels of bioavailable testosterone and IGF-I paralleled genotype-related differences in lumbar spine BMD.

Conclusion: Allelic variation at the NCOA3 locus may contribute to the genetic control of androgenic hormone and IGF levels and vertebral bone mass among older men.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
OSTEOPOROSIS IS A common and debilitating condition among older men. Although osteoporosis is commonly associated with women, osteoporosis in men also represents a substantial clinical and public health problem. Bone mass measurements in National Health and Nutrition Examination Survey III revealed that 1 million to 2 million American men aged 50 yr and older have osteoporosis, and another 8 million to 13 million are at increased risk of osteoporosis and fracture (1). The lifetime risk of suffering a hip, spine, or forearm fracture in a 50-yr-old white man is estimated to be 13% (2). Compared with women, much less is known about the etiology of osteoporosis in men. Recent studies suggest that the relationship between bone mineral density (BMD) and fracture may be different among women and men (3, 4, 5) and that distinct genetic loci may regulate BMD in males and females, suggesting a need to define the gender-specific etiology of low bone mass and osteoporosis in men (6). Several gene allelic variants have been implicated in the control of BMD and osteoporosis risk among women, but the genetic variation contributing to normal variation in BMD among men is less well defined.

Nuclear receptor coactivator-3 (NCOA3), is a member of the p160 nuclear receptor coactivator family that facilitates receptor transcriptional activation function and thereby steroid hormone sensitivity (7). NCOA3 functions by interacting with transcription factors and by recruiting histone acetyltransferase and methyltransferases to the promoter region of target genes, thereby mediating chromatin remodeling and DNA transcription (7). Recent experiments indicate that NCOA3 is required for normal somatic growth in animals, an effect that has been attributed in part to IGF-I gene expression and response (8, 9). Furthermore, a CAG/CAA (glutamine) repeat polymorphism in the NCOA3 gene has been related to prostate and breast cancers as well as androgen insensitivity syndrome, suggesting that genetic variation at this locus may alter sex steroid hormone sensitivity (10, 11, 12). We hypothesized that variation in numbers of CAG/CAA repeat length in the NCOA3 gene may also affect skeletal size and BMD in men. Thus, the present study examined the relationships between the CAG/CAA (glutamine) length variation at the NCOA3 locus, sex steroid hormone and IGF-I levels, and BMD in a cohort of older Caucasian men.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
The present sample was drawn from 523 Caucasian and African-American men who participated in the Study of Osteoporotic Risk in Men, a study of the determinants of bone density in men aged 50 yr and older (13). Participants were recruited primarily from population-based lists of age-eligible voters in the Monongahela Valley (30 miles southeast of Pittsburgh, PA). African-American men were excluded because of their higher bone density and lower incidence of fractures. Men who were unable to walk without assistance of another person, had undergone a bilateral hip replacement, or were being treated for osteoporosis were excluded as well. Of the 523 men who participated in the baseline examination, 263 provided peripheral blood leukocytes for DNA extraction and genotyping at subsequent clinic visits and form the basis of the present analyses. Written informed consent was obtained from all participants, and the protocol was approved by University of Pittsburgh Institutional Review Board.

Genotyping

High-molecular-weight genomic DNA was isolated from peripheral lymphocytes harvested from the EDTA anticoagulated whole blood using the salting-out procedure (14). To determine the length of the CAG microsatellite of the NCOA3 gene, we amplified DNA samples with flanking primers (5'-FAM-CACTTCCGACAACAGAGGGTGG-3' and 5'-TATGGAAACTGTTGCGGAGGAG-3). Briefly, the PCR mixture contained 1x buffer (Invitrogen, Carlsbad, CA) with 1.5 mM MgCl2, deoxynucleotide triphosphates (each at 1.25 mM), 20 pmol of each primer, and target DNA (40 ng). The PCR amplification parameters were a 4-min initial denaturation at 94 C and 35 cycles each of 30 sec at 94 C, 30 sec at 60 C, and 45 sec at 72 C, followed by a 7-min final elongation cycle at 72 C. All of the PCRs were performed in a Tetrad thermocycler (MJ Research, Waltham, MA). A 200-bp fragment (including the NCOA3 microsatellite) was sequenced in a subset of homozygous individuals by Polymorphic DNA Technologies, Inc (Alameda, CA) using ABI BigDye Terminator 3.1 chemistry and the ABI 3730 XL DNA analyzer (Applied Biosystems, Foster City, CA). The number of repeats for each allele was determined using Sequencher 4.5 sequence analysis software (Genecodes, Ann Arbor, MI).

Bone densitometry

BMD of the total hip and its subregions (femoral neck and trochanter) and anterioposterior lumbar spine (L2-L4) was measured with dual x-ray absorptiometry using either Hologic QDR-1000 or QDR-2000 densitometers (Hologic, Inc., Bedford, MA). The correlation coefficient for BMD measurements in 10 men scanned on the two densitometers was r = 0.98.

Endocrine assays

Blood samples were collected in the morning after an overnight fast and stored at –70 C until first thawed for hormone assays. Samples for sex steroid hormone analysis were sent directly from storage to the analytical laboratory (Esoterix Endocrinology, Calabasas Hills, CA) without thawing. Total testosterone was measured by radioimmunoassay after extraction and purification by column chromatography (15). Estradiol was measured by RIA after extraction and purification by column chromatography (16). Bioavailable testosterone and bioavailable estradiol were determined by separation of the SHBG-bound steroid from albumin bound and free steroid with ammonium sulfate as described by Mayes and Nugent (17). Aliquots of serum samples were incubated with either H3-testosterone or H3-estradiol. SHBG was precipitated by the addition of ammonium sulfate and the samples centrifuged. Aliquots of the supernatant containing the non-SHBG-bound steroids were removed for scintillation counting. The bioavailable steroid concentration was then derived from the product of the total serum steroid and the percent non-SHBG bound steroid determined from the separation procedure. The ranges of intra- and interassay coefficients of variation (CVs) and the corresponding concentrations, respectively, are 0.72% (2733.33 ng/dl) to 5.17% (12.35 ng/dl) and 5.6% (2557 ng/dl) to 9.9% (12.6 ng/dl) for total testosterone; 3–4 and 10.7% (8.0 ng/dl) to 15.5 (140 ng/dl) for bioavailable testosterone; 5.5% (2.86 ng/dl) to 6.2% (31.4 ng/dl) and 9.2% (110 ng/dl) to 10.9% (54 ng/dl) for total estradiol; 0.8–8.9 and 3.4–7.9% for bioavailable estradiol; 2.7% (61.9 nmol/liter) to 4.7% (166.7 nmol/liter), and 5.9% (184 nmol/liter) to 8.2% (64.8 nmol/liter) for SHBG.

Serum IGF-I was measured using a double-antibody RIA (Nichols Institute, San Juan Capistrano, CA) after acid-ethanol cryoprecipitation extraction to remove IGF binding proteins (IGFBPs) as reported previously (18). The calculated sensitivity of the assay is 0.06 ng/ml. The cross-reactivity with IGF-II is less than 0.5%. The ranges of inter- and intraassay CV and the corresponding concentrations are 4.1% (292.2 ng/ml) to 6.5% (41.4 ng/ml) and 6.5% (223 ng/ml) and 9.4% (63.4 ng/ml), respectively.

Serum concentrations of IGFBP-3 were assayed using the active IGFBP-3 IRMA (Diagnostic Systems Laboratories, Webster, TX). This kit uses a two-site immunoradiometric principle to directly measure nonglycosylated IGFBP-3. The ranges of inter- and intraassay CV and the corresponding concentrations are 5.1% (2.7 mg/liter) to 13% (1.0 mg/liter) and 5.5% (2.9 mg/liter) to 17% (0.8 mg/liter), respectively. The sensitivity is 0.5 ng/ml.

Other measures

A self-administered questionnaire was used to collect information on age, alcohol consumption per week, current smoking status, calcium and thiazide-diuretic intake, steroid use, engagement in rigorous exercise per week, and self-reporting reported health status (excellent, good, fair, poor, very poor).

Body weight was measured to the nearest 0.1 kg without shoes and heavy outer clothing on a calibrated balance beam scale. Height was measured twice to the nearest 0.1 cm after removal of shoes using a wall-mounted Harpenden stadiometer (Holtain, Dyved, UK). The average of height measurements was used in statistical analysis. Body mass index was calculated as weight in kilogram divided by height in square meters.

Statistical analysis

Allele frequencies were estimated by gene counting. Hardy-Weinberg equilibrium was tested by a {chi}2 goodness of fit statistic. ANOVA was used to test for differences in continuous variables across NCOA3 genotype. We analyzed differences in subject characteristics according to the number of copies (0, 1, or 2) of the most common repeat (29 CAG/CAA repeats). We adjusted for age, body weight, and height using analysis of covariance (ANCOVA). {chi}2 Statistics were used to test for differences in dichotomous variables across genotype. We also performed multiple regression analysis with backward elimination to determine the independent contribution of NCOA3 alleles to BMD and hormone levels. We used the partial coefficients of determination (r2) to estimate the independent contribution of the NCOA3 polymorphism to the total phenotypic variance. We included age, body weight, and height in the models to control for their potential confounding effects with the phenotypic measures. Statistical analyses were performed with the Statistical Analysis System (SAS) software (version 8.2; SAS Institute Inc., Cary, NC).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
We observed four alleles and seven genotypes in this sample of older Caucasian men (Table 1Go). The 29 repeat allele was the most common allele (53.2%), followed by 28 (35.6%) and 26 (10.8%) repeats. Seventy-five percent of the participants had at least one 29 repeat allele. We compared the characteristics of men with 0 (n = 67), 1 (n = 112), or 2 (n = 84) copies of the 29 CAG/CAA repeats.


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  		TABLE 1. Frequency of NCOA3 alleles and genotypes

 
The study sample had a mean age of 67 yr (range 51–84). Age, body weight, alcohol consumption, smoking status, exercise, health status, thiazide-diuretic, calcium use, and vitamin D use showed no difference across NCOA3 genotypes. Height was the only characteristic that significantly differed across genotypes (P = 0.0436). Men with two copies of the 29 repeat alleles were over 2 cm taller than men without this allele (Table 2Go).


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  		TABLE 2. Characteristics of men by NCOA3 genotype

 
Serum levels of bioavailable testosterone and bioavailable estradiol in our cohort were similar to values reported in a large population studies of older men (19). Serum levels of bioavailable testosterone and SHBG were significantly associated with NCOA3 genotype (Table 3Go). Men with zero copies of the 29 repeat allele had significantly higher bioavailable testosterone (P = 0.01) and lower SHBG (P < 0.01) than men with either one or two copies of this allele. In a linear regression analysis (data not shown), genotype explained 1.7 and 3.7% of total phenotypic variance in serum levels of bioavailable testosterone (P = 0.02) and SHBG (P < 0.001), respectively. In contrast, serum levels of total testosterone and total and bioavailable estradiol were similar among the three NCOA3 genotypes.


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  		TABLE 3. Serum hormone levels in older men according to NCOA3 genotype

 
Serum levels of IGF-I correlated positively with BMD at the lumbar spine (r = 0.16, P < 0.01) and femoral neck (r = 0.45, P < 0.05). Serum IGF-I levels differed significantly across NCOA3 genotype (Table 3Go). Men with the 29/29 genotype had 15 and 11% lower concentrations of IGF-I, compared with men with zero or one copies of this allele, respectively. NCOA3 genotype was unrelated to the major IGF-I binding protein, IGFBP-3. Bioavailable testosterone was positively (r = 0.27; P < 0.001) and SHBG inversely (r = –0.33; P < 0.001) correlated with IGF-I levels. Thus, we adjusted NCOA3 analyses further for bioavailable testosterone and SHBG. The difference in IGF-I levels across NCOA3 genotype was attenuated and no longer statistically significant (P = 0.08) after adjusting for bioavailable testosterone and SHBG.

We also observed an association between NCOA3 genotype and lumbar spine, but not proximal femur, BMD (Table 4Go). Men with the 29/29 genotype had 6% or nearly 0.5 SD lower spine BMD, compared with those with no 29 repeat alleles, whereas heterozygous men had intermediate BMD. This association was independent of age, weight, and height. In a multiple linear regression analysis, age, body weight, serum IGF-I and bioavailable estradiol, and number of copies of the 29 repeat allele explained 26.3% of the total phenotypic variance in lumbar spine BMD (data not shown). Examination of the partial coefficients of determination revealed that 3.2% of the phenotypic variance in lumbar spine BMD could be attributed to NCOA3 alleles (P < 0.01) and that this effect was similar in magnitude to serum IGF-I levels (r2 = 3.3%) and age (r2 = 2.8%).


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  		TABLE 4. BMD by NCOA3 genotype

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Inheritance plays an important role in the determination of BMD and the risk of osteoporosis and fracture (20, 21, 22). This heritable influence on BMD and related phenotypes is detected early during childhood before peak BMD is reached, persists well into the eighth decade of life, and has been demonstrated in women and men. Genome-wide linkage studies have implicated quantitative trait loci for BMD on several chromosomes in humans, but the specific genes at these chromosomal sites remain largely undefined (23). There is also evidence of a small but significant influence of variation at several loci and BMD including the vitamin D receptor (VDR), estrogen receptor-{alpha} (ESR1), type I collagen (COL1A1), low-density lipoprotein receptor-related protein 5 (LRP5),and several others (20, 21, 22, 24, 25, 26, 27). However, the majority of these studies have been in women, and our understanding of the genetic contributions to male skeletal health remains very limited. The importance of elucidating the genetic causation of BMD variation in men is supported by animal studies showing that at least some of the genetic loci for BMD are gender specific (6). The present study is the first, to our knowledge, to implicate the NCOA3 locus as a genetic determinant of BMD in men, although a previous report (28) noted an association between NCOA3 genotype and calcaneal ultrasound in women.

An interesting observation in the present study was that 29 CAG/CAA (glutamine) repeats in the NCOA3 gene was significantly and independently associated with lumbar spine, but not proximal femur, BMD. Recent studies in inbred strains of mice indicate that the genetic regulation of bone mass and bone strength is skeletal site specific (29). Moreover, mice lacking another member of the p160 steroid receptor coactivator family, NCOA1, have markedly reduced skeletal sensitivity to sex steroid hormones, and this effect appears to be restricted to the trabecular and not cortical bone compartment (30, 31). The present and these previous findings suggest that different genetic loci, acting either alone or together with environmental factors, influence bone mass at the proximal femur and lumbar spine.

To our knowledge, an association between the NCOA3 CAG/CAA repeat polymorphism and height has not been reported before and suggests a link between allelic variation at this locus and linear bone growth. These findings are consistent with experiments demonstrating that NCOA3 is an important modulator of mammalian cell growth (32) and is required for normal pubertal development and somatic growth during sexual maturation and into adulthood in mice (8, 9). Nevertheless, NCOA3 alleles remained significantly associated with lumbar spine BMD after adjustment for height suggesting that body size was unlikely to be a confounding factor in our analyses.

Serum levels of sex steroid hormones vary widely among individuals and with aging (33), influencing the risk of several common conditions including osteoporosis. Inherited genetic variants and environmental factors modulate sex steroid hormone metabolism (34), but little is known about the specific polymorphisms that contribute to variation in sex steroid hormone concentrations. NCOA3 encodes a nuclear receptor coactivator protein that enhances androgen/estrogen receptor signaling. Because the regulation of circulating sex steroid hormone levels is governed by negative and positive feedback loops, allelic variants in NCOA3 may contribute to interindividual differences in the sensitivity to feedback regulation and thereby influence sex steroid hormone metabolism. Indeed, we found that men without the 29 CAG/CAA allele had significantly increased serum levels of bioavailable testosterone, compared with men who were homozygous for this allele. In a previous case-control study in which men with shorter CAG/CAA repeats were more likely to have androgen insensitivity (11). Men without the 29 CAG/CAA allele also had significantly decreased serum concentrations of SHBG. Thus, NCOA3 alleles may influence the levels of bioavailable testosterone in blood by affecting the expression and production of SHBG, a major binding protein of testosterone.

NCOA3 genotype explained less than 4% of the total phenotypic variance in bioavailable testosterone levels in our study, indicating that additional allelic variants at the NCOA3 locus or other steroidogenic loci contribute to the wide variance in endogenous testosterone levels among older men. Nonetheless, when we added serum levels of bioavailable testosterone and SHBG to a multiple regression model, NCOA3 genotype remained a significant independent predictor of lumbar spine BMD. Furthermore, bioavailable testosterone and SHBG were not significantly related to lumbar spine BMD in our sample of older men. Thus, it is possible that NCOA3 alleles may influence lumbar spine BMD through mechanisms not involving sex steroid hormones.

IGF-I is an important regulator of bone growth, and BMD (35) has been implicated in idiopathic male osteoporosis (36, 37) and was a significant and positive correlate of BMD in the present study. At least part of the effect of NCOA3 on normal somatic growth has been attributed to altered regulation of IGF-I gene expression and a decreased cellular response to IGF-I (8, 9). Similar mechanisms might underline the association between NCOA3 genotype and BMD. Nonetheless, both NCOA3 genotype and serum IGF-I were significantly associated with BMD in multivariate regression analyses, suggesting that both factors made an independent contribution to BMD variation.

As much as 60% of the variation in serum IGF-I levels may be explained by genetic factors (38). The genetic loci contributing to serum IGF-I variation is not well defined in humans, although several putative loci for the IGF-I phenotype are beginning to emerge in mice (39). The present results suggest that NCOA3 alleles may contribute to IGF-I levels, an observation that is consistent with at least one other recent report in women (40). The association between NCOA3 genotype and IGF-I was no longer statistically significant in our study, however, after adjusting for serum concentrations of SHBG and bioavailable testosterone, a known stimulator of IGF-I levels (41). These observations suggest a complex interplay among NCOA3 genotype, androgens, and IGF-I in the regulation of bone mass in men.

The molecular mechanisms by which the glutamine repeat polymorphism might influence NCOA3 function are unknown. Variable polyglutamine tracts encoded by CAG repeats in the androgen receptor is known to influence androgen receptor transcriptional activation function (42). The variable polyglutamine tract in NCOA3 occurs within the intrinsic transcriptional activation domain in the C terminus and might influence transactivation of NCOA3 target genes (7). Nonetheless, functional studies are needed to test whether the CAG repeat polymorphism directly alters NCOA3 function or is in linkage disequilibrium with other functional variation in the regulatory or coding regions of this gene.

In conclusion, the present data suggest that a CAG/CAA (glutamine) repeat polymorphism within the NCOA3 gene, or a closely linked allelic variant, contributes to the genetic influence on lumbar spine BMD in middle aged and elderly men. Further studies are needed to confirm these observations to define the molecular mechanisms involved and evaluate the relationship between NCOA3 gene variation and the incidence of fracture in men.


   Footnotes
 
This work was supported by United States Public Health Service Grants AR 35582, DK 46204, and 1P60 AR44811.

First Published Online November 1, 2005

Abbreviations: ANCOVA, Analysis of covariance; BMD, bone mineral density; CV, coefficient of variation; IGFBP, IGF binding protein; NCOA, nuclear receptor coactivator.

Received April 20, 2005.

Accepted October 24, 2005.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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