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Genetic variation in TRPS1 may regulate hip geometry as well as bone mineral density.

ABSTRACT: Trps1 has been proposed as a candidate gene for a mouse bone mineral density (BMD) QTL on Chromosome (Chr) 15, but it remained unclear if this gene was associated with BMD in humans. We used newly available data and advanced bioinformatics techniques to confirm that Trps1 is the most likely candidate gene for the mouse QTL. In short, by combining the raw genetic mapping data from two F2 generation crosses of inbred strains of mice, we narrowed the 95% confidence interval of this QTL down to the Chr 15 region spanning from 6 to 24cM. This region contains 131 annotated genes. Using block haplotyping, all other genes except Trps1 were eliminated as candidates for this QTL. We then examined associations of 208 SNPs within 10kb of TRPS1 with BMD and hip geometry, using human genome-wide association study (GWAS) data from the GEFOS consortium. After correction for multiple testing, six TRPS1 SNPs were significantly associated with femoral neck BMD (P=0.0015-0.0019; adjusted P=0.038-0.048). We also found that three SNPs were highly associated with femoral neck width in women (rs10505257, P=8.6×10(-5), adjusted P=2.15×10(-3); rs7002384, P=5.5×10(-4), adjusted P=01.38×10(-2)). In conclusion, we demonstrated that combining association studies in humans with murine models provides an efficient strategy to identify new candidate genes for bone phenotypes.

SUBMITTER: Ackert-Bicknell CL

PROVIDER: S-EPMC3322322 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Genetic variation in TRPS1 may regulate hip geometry as well as bone mineral density.

Ackert-Bicknell Cheryl L CL Demissie Serkalem S Tsaih Shirng-Wern SW Beamer Wesley G WG Cupples L Adrienne LA Paigen Beverly J BJ Hsu Yi-Hsiang YH Kiel Douglas P DP Karasik David D

Bone 20120128 5

Trps1 has been proposed as a candidate gene for a mouse bone mineral density (BMD) QTL on Chromosome (Chr) 15, but it remained unclear if this gene was associated with BMD in humans. We used newly available data and advanced bioinformatics techniques to confirm that Trps1 is the most likely candidate gene for the mouse QTL. In short, by combining the raw genetic mapping data from two F2 generation crosses of inbred strains of mice, we narrowed the 95% confidence interval of this QTL down to the ...[more]

PMID: 22306695

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Project description:BackgroundMuscle weakness is a key factor in the increase risk of falls and might also play a significant role in the increase of risk of hip fracture. Computed tomography-measured muscle size and muscle density are well-established imaging biomarkers used in studies of physical function, frailty or cancer, but limited to hip fracture. In particular, it is warranted to have a better understanding of the performance of muscle size and density in the discrimination of acute hip fractures. We also aim to determine age-related differences of muscle size and density in healthy controls and hip fracture patients.MethodsFour hundred thirty-eight low-energy acute hip fracture cases and 316 healthy controls from the China Action on Spine and Hip Status study were included in the study. Muscle cross-sectional area and density were measured for the gluteus maximus and gluteus medius and minimus. Areal bone mineral density (aBMD) of the femoral neck and total hip was measured. Using propensity score matching, we generated three samples with cases and controls matched for age, body mass index, and gender: femoral neck fracture (FNF), intertrochanteric fracture (ITF), and any hip fracture vs. controls, respectively.ResultsHandgrip strength, gluteus muscle area and density, and bone parameters of the matched hip fracture groups were lower than those of the correspondence control groups, respectively (P < 0.05). The univariate analysis showed that associations of aBMD with FNF and with ITF were significantly weaker than associations between fracture and muscle parameters. Gluteus medius and minimus muscle density showed the highest areas under the curve (AUC) with FNF (0.88, 95% confidence interval, 0.85-0.92) and trochanteric fracture (0.95, 95% confidence interval, 0.92-0.97). The model including all muscle and bone parameters provided the highest AUC (FNF: AUC 0.912; ITF: AUC 0.958), and AUC results of another selected model without muscle density showed that association with fracture significantly dropped (FNF: AUC 0.755; ITF: AUC 0.858). Separate results for the two age groups younger and older than 70 years showed no age-related significant differences in discriminate models.ConclusionsMuscle density performs better than aBMD from hip computed tomography X-ray absorptiometry and muscle size in discrimination of hip fracture. Combination of aBMD and muscle density provided the best discrimination. The integration of muscle assessments may trigger a paradigm shift in hip fracture prediction. Gluteus muscle density should also be evaluated as treatment outcome.

Project description:SummaryWe tested whether two genetic variants were associated with BMD at multiple clinically relevant skeletal sites in Caucasians. We found that variant rs7776725 is consistently associated with hip, spine, wrist and whole-body BMD, which highlights the potential importance of this variant or linked variants for osteoporosis.IntroductionA recent genome-wide association study identified two single nucleotide polymorphisms (SNPs), rs7776725 and rs1721400, that were associated with bone mineral density (BMD) variation at the radius, tibia and calcaneus in a Korean population. In this study, we aimed to test whether the association of these two genetic variants can be replicated in Caucasians and whether their association with BMD can be extended to other clinically relevant skeletal sites.MethodsWe performed this study in two large cohorts of unrelated US Caucasians. Area BMD at the hip, spine, wrist (ultra-distal radius) and whole body were measured with Hologic dual-energy X-ray absorptiometer. SNPs were genotyped with Affymetrix human genome-wide genotyping arrays. Association analyses were performed using PLINK.ResultsWe detected highly significant association (combined p = 1.42 × 10(-16)) of rs7776725 with wrist BMD but only borderline association signal (combined p = 0.017) for rs1721400 with wrist BMD. In addition, we found that rs7776725 was associated with BMD at the hip, spine and whole body. At the FAM3C gene locus where rs7776725 was located, we identified several other SNPs (rs4727922, rs1803389, rs718766 and rs7793554) that were also associated with BMD.ConclusionsThis is the first follow-up association study of rs7776725 and rs1721400 with BMD. The rs7776725 showed consistent association with BMD at multiple clinically important skeletal sites, which highlighted the potential importance of rs7776725 or linked SNPs for risk of osteoporosis. Further in-depth re-sequencing studies and functional assays are necessary to elucidate the underlying mechanisms.

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Genetic variation in TRPS1 may regulate hip geometry as well as bone mineral density.

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Genetic variation in TRPS1 may regulate hip geometry as well as bone mineral density.

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