Dataset Information

WNT16 influences bone mineral density, cortical bone thickness, bone strength, and osteoporotic fracture risk.

ABSTRACT: We aimed to identify genetic variants associated with cortical bone thickness (CBT) and bone mineral density (BMD) by performing two separate genome-wide association study (GWAS) meta-analyses for CBT in 3 cohorts comprising 5,878 European subjects and for BMD in 5 cohorts comprising 5,672 individuals. We then assessed selected single-nucleotide polymorphisms (SNPs) for osteoporotic fracture in 2,023 cases and 3,740 controls. Association with CBT and forearm BMD was tested for ?2.5 million SNPs in each cohort separately, and results were meta-analyzed using fixed effect meta-analysis. We identified a missense SNP (Thr>Ile; rs2707466) located in the WNT16 gene (7q31), associated with CBT (effect size of -0.11 standard deviations [SD] per C allele, P = 6.2 × 10(-9)). This SNP, as well as another nonsynonymous SNP rs2908004 (Gly>Arg), also had genome-wide significant association with forearm BMD (-0.14 SD per C allele, P = 2.3 × 10(-12), and -0.16 SD per G allele, P = 1.2 × 10(-15), respectively). Four genome-wide significant SNPs arising from BMD meta-analysis were tested for association with forearm fracture. SNP rs7776725 in FAM3C, a gene adjacent to WNT16, was associated with a genome-wide significant increased risk of forearm fracture (OR = 1.33, P = 7.3 × 10(-9)), with genome-wide suggestive signals from the two missense variants in WNT16 (rs2908004: OR = 1.22, P = 4.9 × 10(-6) and rs2707466: OR = 1.22, P = 7.2 × 10(-6)). We next generated a homozygous mouse with targeted disruption of Wnt16. Female Wnt16(-/-) mice had 27% (P<0.001) thinner cortical bones at the femur midshaft, and bone strength measures were reduced between 43%-61% (6.5 × 10(-13)

SUBMITTER: Zheng HF

PROVIDER: S-EPMC3390364 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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WNT16 influences bone mineral density, cortical bone thickness, bone strength, and osteoporotic fracture risk.

Zheng Hou-Feng HF Tobias Jon H JH Duncan Emma E Evans David M DM Eriksson Joel J Paternoster Lavinia L Yerges-Armstrong Laura M LM Lehtimäki Terho T Bergström Ulrica U Kähönen Mika M Leo Paul J PJ Raitakari Olli O Laaksonen Marika M Nicholson Geoffrey C GC Viikari Jorma J Ladouceur Martin M Lyytikäinen Leo-Pekka LP Medina-Gomez Carolina C Rivadeneira Fernando F Prince Richard L RL Sievanen Harri H Leslie William D WD Mellström Dan D Eisman John A JA Movérare-Skrtic Sofia S Goltzman David D Hanley David A DA Jones Graeme G St Pourcain Beate B Xiao Yongjun Y Timpson Nicholas J NJ Smith George Davey GD Reid Ian R IR Ring Susan M SM Sambrook Philip N PN Karlsson Magnus M Dennison Elaine M EM Kemp John P JP Danoy Patrick P Sayers Adrian A Wilson Scott G SG Nethander Maria M McCloskey Eugene E Vandenput Liesbeth L Eastell Richard R Liu Jeff J Spector Tim T Mitchell Braxton D BD Streeten Elizabeth A EA Brommage Robert R Pettersson-Kymmer Ulrika U Brown Matthew A MA Ohlsson Claes C Richards J Brent JB Lorentzon Mattias M

PLoS genetics 20120705 7

We aimed to identify genetic variants associated with cortical bone thickness (CBT) and bone mineral density (BMD) by performing two separate genome-wide association study (GWAS) meta-analyses for CBT in 3 cohorts comprising 5,878 European subjects and for BMD in 5 cohorts comprising 5,672 individuals. We then assessed selected single-nucleotide polymorphisms (SNPs) for osteoporotic fracture in 2,023 cases and 3,740 controls. Association with CBT and forearm BMD was tested for ∼2.5 million SNPs ...[more]

PMID: 22792071

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Project description:ImportanceScreening for osteoporosis with bone mineral density (BMD) is recommended for older adults. It is unclear whether repeating a BMD screening test improves fracture risk assessment.ObjectivesTo determine whether changes in BMD after 4 years provide additional information on fracture risk beyond baseline BMD and to quantify the change in fracture risk classification after a second BMD measure.Design, setting, and participantsPopulation-based cohort study involving 310 men and 492 women from the Framingham Osteoporosis Study with 2 measures of femoral neck BMD taken from 1987 through 1999.Main outcomes and measuresRisk of hip or major osteoporotic fracture through 2009 or 12 years following the second BMD measure.ResultsMean age was 74.8 years. The mean (SD) BMD change was -0.6% per year (1.8%). Throughout a median follow-up of 9.6 years, 76 participants experienced an incident hip fracture and 113 participants experienced a major osteoporotic fracture. Annual percent BMD change per SD decrease was associated with risk of hip fracture (hazard ratio [HR], 1.43 [95% CI, 1.16 to 1.78]) and major osteoporotic fracture (HR, 1.21 [95% CI, 1.01 to 1.45]) after adjusting for baseline BMD. At 10 years' follow-up, 1 SD decrease in annual percent BMD change compared with the mean BMD change was associated with 3.9 excess hip fractures per 100 persons. In receiver operating characteristic (ROC) curve analyses, the addition of BMD change to a model with baseline BMD did not meaningfully improve performance. The area under the curve (AUC) was 0.71 (95% CI, 0.65 to 0.78) for the baseline BMD model compared with 0.68 (95% CI, 0.62 to 0.75) for the BMD percent change model. Moreover, the addition of BMD change to a model with baseline BMD did not meaningfully improve performance (AUC, 0.72 [95% CI, 0.66 to 0.79]). Using the net reclassification index, a second BMD measure increased the proportion of participants reclassified as high risk of hip fracture by 3.9% (95% CI, -2.2% to 9.9%), whereas it decreased the proportion classified as low risk by -2.2% (95% CI, -4.5% to 0.1%).Conclusions and relevanceIn untreated men and women of mean age 75 years, a second BMD measure after 4 years did not meaningfully improve the prediction of hip or major osteoporotic fracture. Repeating a BMD measure within 4 years to improve fracture risk stratification may not be necessary in adults this age untreated for osteoporosis.

Project description:BackgroundOsteoporosis is diagnosed by the measurement of bone mineral density, which is a highly heritable and multifactorial trait. We aimed to identify genetic loci that are associated with bone mineral density.MethodsIn this genome-wide association study, we identified the most promising of 314 075 single nucleotide polymorphisms (SNPs) in 2094 women in a UK study. We then tested these SNPs for replication in 6463 people from three other cohorts in western Europe. We also investigated allelic expression in lymphoblast cell lines. We tested the association between the replicated SNPs and osteoporotic fractures with data from two studies.FindingsWe identified genome-wide evidence for an association between bone mineral density and two SNPs (p<5x10(-8)). The SNPs were rs4355801, on chromosome 8, near to the TNFRSF11B (osteoprotegerin) gene, and rs3736228, on chromosome 11 in the LRP5 (lipoprotein-receptor-related protein) gene. A non-synonymous SNP in the LRP5 gene was associated with decreased bone mineral density (rs3736228, p=6.3x10(-12) for lumbar spine and p=1.9x10(-4) for femoral neck) and an increased risk of both osteoporotic fractures (odds ratio [OR] 1.3, 95% CI 1.09-1.52, p=0.002) and osteoporosis (OR 1.3, 1.08-1.63, p=0.008). Three SNPs near the TNFRSF11B gene were associated with decreased bone mineral density (top SNP, rs4355801: p=7.6x10(-10) for lumbar spine and p=3.3x10(-8) for femoral neck) and increased risk of osteoporosis (OR 1.2, 95% CI 1.01-1.42, p=0.038). For carriers of the risk allele at rs4355801, expression of TNFRSF11B in lymphoblast cell lines was halved (p=3.0x10(-6)). 1883 (22%) of 8557 people were at least heterozygous for these risk alleles, and these alleles had a cumulative association with bone mineral density (trend p=2.3x10(-17)). The presence of both risk alleles increased the risk of osteoporotic fractures (OR 1.3, 1.08-1.63, p=0.006) and this effect was independent of bone mineral density.InterpretationTwo gene variants of key biological proteins increase the risk of osteoporosis and osteoporotic fracture. The combined effect of these risk alleles on fractures is similar to that of most well-replicated environmental risk factors, and they are present in more than one in five white people, suggesting a potential role in screening.

Project description:We performed a systematic review on the effect of drug holidays (discontinuation) on bone mineral density (BMD) and fracture risk. Bisphosphonate discontinuation may be considered for women who do not have low hip BMD after 3-5 years of initial treatment, while women who have low hip BMD may benefit from treatment continuation.IntroductionWe performed a systematic review and meta-analysis on the effect of drug holidays (discontinuation) on BMD and fracture risk.MethodsWe searched PubMed, Embase, and Cochrane Library databases to locate controlled clinical trials and cohort studies evaluating the effect of drug holidays/discontinuation versus osteoporosis treatment continuation. We performed random-effects meta-analyses of hazard ratios of hip and any clinical osteoporotic fracture for individuals who discontinued bisphosphonates compared to persistent users.ResultsThirteen records reporting results from eight different studies met inclusion criteria. The FLEX study found a reduced clinical vertebral fracture risk with 10 years of alendronate therapy compared to 5 (RR 0.45, 95% CI 0.24-0.85), and the HORIZON extension studies found a reduced risk of morphometric vertebral fracture with 6 years of zoledronic acid therapy compared to 3 (OR = 0.51, 95% CI 0.26-0.95); subgroup analyses showed that women with low hip BMD T-scores after the initial treatment period benefitted from continued treatment in terms of reduced vertebral fracture risk. Meta-analysis of adjusted hazard ratios of hip and any clinical osteoporotic fracture for women who discontinued bisphosphonates revealed no significant differences in the risk of hip fracture (summary estimate of HR 1.09, 95% CI 0.87-1.37) or any clinical fracture (summary estimate of HR 1.13, 95% CI 0.75-1.70) compared to persistent users.ConclusionsBisphosphonate discontinuation may be considered for women who do not have low hip BMD after 3 to 5 years of initial treatment, while women who have low hip BMD may benefit from treatment continuation.

Dataset Information

WNT16 influences bone mineral density, cortical bone thickness, bone strength, and osteoporotic fracture risk.

Publications

WNT16 influences bone mineral density, cortical bone thickness, bone strength, and osteoporotic fracture risk.

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