Dataset Information

Polymorphisms in genes involved in the NF-?B signalling pathway are associated with bone mineral density, geometry and turnover in men.

ABSTRACT: INTRODUCTION:In this study, we aimed to investigate the association between single nucleotide polymorphisms (SNPs) within two genes involved in the NF-?B cascade (GPR177 and MAP3K14) and bone mineral density (BMD) assessed at different skeletal sites, radial geometric parameters and bone turnover. METHODS:Ten GPR177 SNPs previously associated with BMD with genome-wide significance and twelve tag SNPs (r(2)?0.8) within MAP3K14 (±10 kb) were genotyped in 2359 men aged 40-79 years recruited from 8 centres for participation in the European Male Aging Study (EMAS). Measurement of bone turnover markers (PINP and CTX-I) in the serum and quantitative ultrasound (QUS) at the calcaneus were performed in all centres. Dual energy X-ray absorptiometry (DXA), at the lumbar spine and hip, and peripheral quantitative computed tomography (pQCT), at the distal and midshaft radius, were performed in a subsample (2 centres). Linear regression was used to test for association between the SNPs and bone measures under an additive genetic model adjusting for study centre. RESULTS:We validated the associations between SNPs in GPR177 and BMD(a) previously reported and also observed evidence of pleiotrophic effects on density and geometry. Rs2772300 in GPR177 was associated with increased total hip and LS BMD(a), increased total and cortical vBMD at the radius and increased cortical area, thickness and stress strain index. We also found evidence of association with BMD(a), vBMD, geometric parameters and CTX-I for SNPs in MAP3K14. None of the GPR177 and MAP3K14 SNPs were associated with calcaneal estimated BMD measured by QUS. CONCLUSION:Our findings suggest that SNPs in GPR177 and MAP3K14 involved in the NF-?B signalling pathway influence bone mineral density, geometry and turnover in a population-based cohort of middle aged and elderly men. This adds to the understanding of the role of genetic variation in this pathway in determining bone health.

SUBMITTER: Roshandel D

PROVIDER: S-EPMC3221678 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Polymorphisms in genes involved in the NF-κB signalling pathway are associated with bone mineral density, geometry and turnover in men.

Roshandel Delnaz D Thomson Wendy W Pye Stephen R SR Boonen Steven S Borghs Herman H Vanderschueren Dirk D Huhtaniemi Ilpo T IT Adams Judith E JE Ward Kate A KA Bartfai Gyorgy G Casanueva Felipe F FF Finn Joseph D JD Forti Gianni G Giwercman Aleksander A Han Thang S TS Kula Krzysztof K Lean Michael E ME Pendleton Neil N Punab Margus M Wu Frederick C FC Holliday Kate L KL O'Neill Terence W TW

PloS one 20111121 11

<h4>Introduction</h4>In this study, we aimed to investigate the association between single nucleotide polymorphisms (SNPs) within two genes involved in the NF-κB cascade (GPR177 and MAP3K14) and bone mineral density (BMD) assessed at different skeletal sites, radial geometric parameters and bone turnover.<h4>Methods</h4>Ten GPR177 SNPs previously associated with BMD with genome-wide significance and twelve tag SNPs (r(2)≥0.8) within MAP3K14 (±10 kb) were genotyped in 2359 men aged 40-79 years re ...[more]

PMID: 22132199

Similar Datasets

Project description:BackgroundSevere gonadal steroid deficiency induces bone loss in adult men; however, the specific roles of androgen and estrogen deficiency in hypogonadal bone loss are unclear. Additionally, the threshold levels of testosterone and estradiol that initiate bone loss are uncertain.MethodsOne hundred ninety-eight healthy men, ages 20-50, received goserelin acetate, which suppresses endogenous gonadal steroid production, and were randomized to treatment with 0, 1.25, 2.5, 5, or 10 grams of testosterone gel daily for 16 weeks. An additional cohort of 202 men was randomized to receive these treatments plus anastrozole, which suppresses conversion of androgens to estrogens. Thirty-seven men served as controls and received placebos for goserelin and testosterone. Changes in bone turnover markers, bone mineral density (BMD) by dual-energy x-ray absorptiometry (DXA), and BMD by quantitative computed tomography (QCT) were assessed in all men. Bone microarchitecture was assessed in 100 men.ResultsAs testosterone dosage decreased, the percent change in C-telopeptide increased. These increases were considerably greater when aromatization of testosterone to estradiol was also suppressed, suggesting effects of both testosterone and estradiol deficiency. Decreases in DXA BMD were observed when aromatization was suppressed but were modest in most groups. QCT spine BMD fell substantially in all testosterone-dose groups in which aromatization was also suppressed, and this decline was independent of testosterone dose. Estradiol deficiency disrupted cortical microarchitecture at peripheral sites. Estradiol levels above 10 pg/ml and testosterone levels above 200 ng/dl were generally sufficient to prevent increases in bone resorption and decreases in BMD in men.ConclusionsEstrogens primarily regulate bone homeostasis in adult men, and testosterone and estradiol levels must decline substantially to impact the skeleton.Trial registrationClinicalTrials.gov, NCT00114114.FundingAbbVie Inc., AstraZeneca Pharmaceuticals LP, NIH.

Project description:We sought to determine the influence of single-nucleotide polymorphisms (SNPs) in RANKL, RANK, and OPG on volumetric bone mineral density (vBMD) and bone geometry at the radius in men. Pairwise tag SNPs (r (2) ? 0.8) for RANKL (n = 8), RANK (n = 44), and OPG (n = 22) and five SNPs near RANKL and OPG strongly associated with areal BMD in genomewide association studies were previously genotyped in men aged 40-79 years in the European Male Ageing Study (EMAS). Here, these SNPs were analyzed in a subsample of men (n = 589) who had peripheral quantitative computed tomography (pQCT) performed at the distal (4%) and mid-shaft (50%) radius. Estimated parameters were total and trabecular vBMD (mg/mm(3)) and cross-sectional area (mm(2)) at the 4% site and cortical vBMD (mg/mm(3)); total, cortical, and medullary area (mm(2)); cortical thickness (mm); and stress strain index (SSI) (mm(3)) at the 50% site. We identified 12 OPG SNPs associated with vBMD and/or geometric parameters, including rs10505348 associated with total vBMD (? [95% CI] = 9.35 [2.12-16.58], P = 0.011), cortical vBMD (? [95% CI] = 5.62 [2.10-9.14], P = 0.002), cortical thickness (? [95% CI] = 0.08 [0.03-0.13], P = 0.002), and medullary area (? [95% CI] = -2.90 [-4.94 to -0.86], P = 0.005) and rs2073618 associated with cortical vBMD (? [95% CI] = -4.30 [-7.78 to -0.82], P = 0.015) and cortical thickness (? [95% CI] = -0.08 [-0.13 to -0.03], P = 0.001). Three RANK SNPs were associated with vBMD, including rs12956925 associated with trabecular vBMD (? [95% CI] = -7.58 [-14.01 to -1.15], P = 0.021). There were five RANK SNPs associated with geometric parameters, including rs8083511 associated with distal radius cross-sectional area (? [95% CI] = 8.90 [0.92-16.88], P = 0.029). No significant association was observed between RANKL SNPs and pQCT parameters. Our findings suggest that genetic variation in OPG and RANK influences radius vBMD and geometry in men.

Dataset Information

Polymorphisms in genes involved in the NF-?B signalling pathway are associated with bone mineral density, geometry and turnover in men.

Publications

Polymorphisms in genes involved in the NF-κB signalling pathway are associated with bone mineral density, geometry and turnover in men.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets