New sequence variants associated with bone mineral density

To identify the susceptibility genes for osteoporotic fracture in postmenopausal Chinese women, a two-stage case-control association study using joint analysis was conducted in 1046 patients with nontraumatic vertebra, hip, or distal radius fractures and 2303 healthy controls. First, 113 single-nucleotide polymorphisms (SNPs) in 16 potential osteoporosis candidate genes reported in recent genomewide association studies, meta-analyses studies, large-scale association studies, and functional studies were genotyped in a smallsample-size subgroup consisting of 541 patients with osteoporotic fractures and 554 healthy controls. Variants and haplotypes in SPTBN1, TNFRSF11B, CNR2, LRP4, and ESR1 that have been identified as being associated with osteoporotic fractures were further reanalyzed in the entire case-control group. We identified one SNP in TNFRSF11B (rs3102734), three SNPs in ESR1 (rs9397448, rs2234693, and rs1643821), two SNPs in LRP4 (rs17790156 and rs898604), and four SNPs in SPTBN1 (rs2971886, rs2941583, rs2941584, and rs12475342) were associated with all of the broadly defined osteoporotic fractures. The most significant polymorphism was rs3102734, with increased risk of osteoporotic fractures (odds ratio, 1.35; 95% confidence interval [CI], 1.17-1.55, Bonferroni p ¼ 2.6 Â 10 À4 ). Furthermore, rs3102734, rs2941584, rs12475342, rs9397448, rs2234693, and rs898604 exhibited significant allelic, genotypic, and/or haplotypic associations with vertebral fractures. SNPs rs12475342, rs9397448, and rs2234693 showed significant genotypic associations with hip fractures, whereas rs3102734, rs2073617, rs1643821, rs12475342, and rs2971886 exhibited significant genotypic and/or haplotypic associations with distal radius fractures. Accordingly, we suggest that in addition to the clinical risk factors, the variants in TNFRSF11B, SPTBN1, ESR1, and LRP4 are susceptibility genetic loci for osteoporotic fracture in postmenopausal Chinese women. ß

Section: Study Subjectsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Susceptibility genes for osteoporotic fracture in postmenopausal chinese women

Wang

Zeng

Zhang

et al. 2012

“…In contrast, in a relatively large study of men, no significant association was observed between these three genes and volumetric BMD at the femoral neck and lumbar spine (LS) (34) or trabecular and cortical volumetric BMD at the femoral neck. (35) Nevertheless, recently, SNPs located near RANKL, (36) RANK, (37) and OPG (36,38) also have been associated with BMD in genome-wide association studies (GWAS).…”

Section: Introductionmentioning

confidence: 99%

Genetic variation in the RANKL/RANK/OPG signaling pathway is associated with bone turnover and bone mineral density in men

Roshandel

Holliday

Pye

et al. 2010

The aim of this study was to determine if single-nucleotide polymorphisms (SNPs) in RANKL, RANK, and OPG influence bone turnover and bone mineral density (BMD) in men. Pairwise tag SNPs (r 2 ! 0.8) were selected for RANKL, RANK, and OPG and their 10-kb flanking regions. Selected tag SNPs plus five SNPs near RANKL and OPG, associated with BMD in published genome-wide association studies (GWAS), were genotyped in 2653 men aged 40 to 79 years of age recruited for participation in a population-based study of male aging, the European Male Ageing Study (EMAS). N-terminal propeptide of type I procollagen (PINP) and C-terminal cross-linked telopeptide of type I collagen (CTX-I) serum levels were measured in all men. BMD at the calcaneus was estimated by quantitative ultrasound (QUS) in all men. Lumbar spine and total-hip areal BMD (BMD a ) was measured by dual-energy X-ray absorptiometry (DXA) in a subsample of 620 men. Multiple OPG, RANK, and RANKL SNPs were associated with bone turnover markers. We also identified a number of SNPs associated with BMD, including rs2073618 in OPG and rs9594759 near RANKL. The minor allele of rs2073618 (C) was associated with higher levels of both PINP rs9594759 (C) was associated with lower PINP (b ¼ À1.84, p ¼ .003) and CTX-I (b ¼ À27.02, p ¼ 6.06 Â 10 À8 ) and higher ultrasound BMD at the calcaneus (b ¼ 0.01, p ¼ .037). Our findings suggest that genetic variation in the RANKL/RANK/OPG signaling pathway influences bone turnover and BMD in European men. ß

“…Given that single-nucleotide polymorphisms of SOST that predispose to increased fracture risk and low BMD have been identified recently, (37)(38)(39)(40) the possibility that PTH may be less effective in these populations demands that additional treatment options are made available.…”

mentioning

confidence: 99%

Building bone with a SOST-PTH partnership

Sims

2010

T he discovery of the SOST gene, whose protein product, sclerostin, is an osteocyte-derived inhibitor of Wnt signalling and bone formation, (1,2) has provided a major advance in bone biology. It gives us new insights into the communicating networks among bone cells and, importantly, to new ways of restoring bone once it has been lost. In the current issue of JBMR, Kramer and colleagues complement their earlier demonstration that parathyroid hormone (PTH) inhibits sclerostin expression (3) to show that the anabolic effect of PTH is blunted both in mice overexpressing sclerostin and in SOST null mice. (4) PTH administered by daily injection is the only currently available anabolic therapy for bone. (5,6) While a number of contributing pathways, including direct prodifferentiation (7) and antiapoptotic (8) actions on osteoblasts, as well as couplingrelated activity through the osteoclast, (9) have been proposed, the full mechanism of action of anabolic PTH remains obscure. Another contributory mechanism was introduced by the discovery of sclerostin and its regulation by both PTH and PTH-related protein (PTHrP) via a distal enhancer of the SOST gene. (3,10) The experiments reported by Kramer and colleagues (4) provide further evidence that sclerostin regulation may play a part in PTH anabolic action. Mice overexpressing sclerostin have less bone as a result of decreased bone-formation rate, as described previously. (11) When these mice were treated with a high dose of PTH, sufficient to increase trabecular bone volume (BV/TV) in wild-type mice, no increase in trabecular bone volume was detected despite a robust reduction in sclerostin expression. It is worth noting that even though sclerostin mRNA levels are reduced by PTH in the transgenic model, total sclerostin expression after PTH treatment is still greater than in wild-type mice. This high level of sclerostin expression, the basal phenotype of a mild reduction in bone remodeling, or both impair the effect of PTH on BV/TV. Surprisingly, even though BV/ TV was not increased, all histomorphometric markers of bone formation, as well as the osteoclast surface, were substantially elevated by PTH treatment in the sclerostin transgenic mice to approximately the same extent as that observed in wild-type mice. Thus a question in the sclerostin transgenic model remains as to how PTH can increase bone turnover without altering BV/ TV. Is osteoclast function enhanced? No evidence was obtained for that. An alternative explanation could be that the sclerostin overexpressing mice lay down bone of reduced quality that is easier for osteoclasts to resorb. The quality of bone in the sclerostin overexpressing mouse is not yet known. Resolving this paradox may provide useful information about the interaction between osteoclasts and osteoblasts in the presence of high levels of sclerostin and, presumably, low levels of b-cateninactivated gene transcription.In SOST null mice, as expected from the skeletal abnormalities observed in van Buchem disease and sclerosteosis, (12) trabecular...