| 61. |
- Swanberg, Maria, et al.
(författare)
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Polymorphisms in the macrophage migration inhibitory factor gene and bone loss in postmenopausal women.
- 2010
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Ingår i: Bone. - : Elsevier BV. - 1873-2763 .- 8756-3282. ; 47:2, s. 424-9
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Tidskriftsartikel (refereegranskat)abstract
- Osteoporosis is a severe condition in postmenopausal women and a common cause of fracture. Osteoporosis is a complex disease with a strong genetic impact, but susceptibility is determined by many genes with modest effects and environmental factors. Only a handful of genes consistently associated with osteoporosis have been identified so far. Inflammation affects bone metabolism by interfering with the interplay between bone resorption and formation, and many inflammatory mediators are involved in natural bone remodeling. The cytokine macrophage migration inhibitory factor (MIF) has been shown to affect bone density in rodents, and polymorphisms in the human MIF promoter are associated with inflammatory disorders such as rheumatoid arthritis. We investigated the association of polymorphisms in the MIF gene with bone mineral density (BMD) and bone loss in 1002 elderly women using MIF promoter polymorphisms MIF-CATT(5-8) and rs755622(G/C) located -794 and -173 bp upstream of the transcriptional start site. Bone loss was estimated both by the change in BMD over 5 years and by the levels of bone resorption markers in serum measured at four occasions during a 5-year period. The MIF-CATT(7)/rs755622(C) haplotype was associated with increased rate of bone loss during 5 years at the femoral neck (p<0.05) and total hip (p<0.05). In addition, the MIF-CATT(7)/rs755622(C) haplotype carriers had higher levels of the bone turnover marker serum C-terminal cross-linking telopeptide of type I collagen (S-CTX-I, p<0.01) during the 5 year follow-up period. There was no association between MIF-CATT(7)/rs755622(C) and baseline BMD at femoral neck, total hip or lumbar spine. We conclude that MIF promoter polymorphisms have modest effects on bone remodeling and are associated with the rate of bone loss in elderly women.
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| 62. |
- Tenne, Max, et al.
(författare)
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Degenerative changes at the lumbar spine-implications for bone mineral density measurement in elderly women.
- 2013
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Ingår i: Osteoporosis International. - : Springer Science and Business Media LLC. - 1433-2965 .- 0937-941X. ; 24:4, s. 1419-1428
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Tidskriftsartikel (refereegranskat)abstract
- Degenerative changes of the lumbar spine may lead to misinterpretation of bone mineral density (BMD) measurements and cause underdiagnosis of osteoporosis. This longitudinal study of 1,044 women, 75 years at inclusion and followed for 10 years, shows that identification of apparent degenerative changes on the dual energy X-ray absorptiometry (DXA) scan can increase the proportion diagnosed. INTRODUCTION: In the elderly, degenerative manifestations in the lumbar spine may result in falsely elevated BMD values, consequently missing a large proportion of those with osteoporosis. Our aim was to determine the distribution and impact of degenerative changes on lumbar spine DXA over time and its clinical implications. METHODS: Participants were 1,044 women from the population-based Osteoporosis Risk Assessment cohort. All women were 75 years old at invitation and followed up after 5 years (n = 715) and 10 years (n = 382). Degenerative changes were evaluated visually on the DXA image for each vertebra L1 to L4 (intraobserver precision kappa values of 0.66-0.70). RESULTS: At baseline, apparent degenerative changes were more frequent in the inferior segments of the lumbar spine [5 % (L1), 15 % (L2), 26 % (L3), and 36 % (L4)] and increased over time. At 10 years, the prevalences were 20 % (L1), 39 % (L2), 59 % (L3), 72 % (L4), resulting in a significant increase in overall BMD. In women without apparent degenerative changes, BMD remained stable between 75 and 85 rather than an expected bone loss. At baseline, 37 % had osteoporosis (BMD < -2.5) at L1-L4; exclusion of women with apparent degenerative changes increased this proportion to 47 %. Using L1-L2, which was less prone to degenerative changes, 46 % of women were classified as osteoporotic regardless of degenerative changes. CONCLUSION: Degenerative changes were very common in elderly women, accelerated disproportionately over time, were increasingly frequent from vertebrae L1 to L4, and had significant impact on diagnosing osteoporosis. This suggests that routine reporting of spine BMD at L1-L2 would add valuable information for reassessment and monitoring.
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| 63. |
- Tenne, Max, et al.
(författare)
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Genetic variation in the PTH pathway and bone phenotypes in elderly women: Evaluation of PTH, PTHLH, PTHR1 and PTHR2 genes.
- 2008
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Ingår i: Bone. - : Elsevier BV. - 1873-2763 .- 8756-3282. ; 42, s. 719-727
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Parathyroid hormone (PTH) is a key regulator of calcium metabolism. Parathyroid hormone-like hormone (PTHrP) contributes to skeletal development through regulation of chondrocyte proliferation and differentiation during early bone growth. Both PTH and PTHrP act through the same receptor (PTHR1). A second receptor, PTHR2, has been identified although its function is comparatively unknown. PTH hyper-secretion induces bone resorption, whereas intermittent injection of PTH increases bone mass. To explore the effects of genetic variation in the PTH pathway, we have analysed variations in PTH, PTHLH, PTHR1 and PTHR2 in relation to bone mass and fracture incidence in elderly women. MATERIALS AND METHODS: This study includes 1044 elderly women, all 75 years old, from the Malmö Osteoporosis Prospective Risk Assessment study (OPRA). Single nucleotide polymorphisms (SNPs) from 4 genes and derived haplotypes in the PTH signaling pathway were analysed in 745-1005 women; 6 SNPs in the PTH gene and 3 SNPs each in the PTHLH, PTHR1 and PTHR2 genes were investigated in relation to BMD (assessed at baseline), fracture (434 prevalent fractures of all types over lifetime, self-reported and 174 incident fractures up to 7 years, X-ray verified) and serum PTH. RESULTS AND CONCLUSION: Individually, SNPs in the 4 loci did not show any significant association with BMD. Neither were PTHLH, PTHR1 and PTHR2 polymorphisms associated with fracture. Three of 5 common haplotypes, accounting for >98% of alleles at the PTH locus, were identified as independent predictors of fracture. Haplotype 9 (19%) was suggestive of an association with fractures of any type sustained during lifetime (p=0.018), with carriers of one or more copies of the haplotype having the lowest incidence (p=0.006). Haplotypes 1 (13%) and 5 (37%) and 9 were suggestive of an association with fractures sustained between 50 and 75 years (p=0.02, p=0.013 and p=0.034). Carriers of haplotypes 1 and 5 were more likely to suffer a fracture (haplotype 1, p=0.045; haplotype 5, p=0.008). We conclude, that while further genotyping across the gene is recommended, in this cohort of elderly Swedish women, polymorphisms in PTH may contribute to the risk of fracture through mechanisms that are independent of BMD.
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| 64. |
- Tenne, Max, et al.
(författare)
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Variation in the PTH Gene, Hip Fracture, and Femoral Neck Geometry in Elderly Women.
- 2010
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Ingår i: Calcified Tissue International. - : Springer Science and Business Media LLC. - 1432-0827 .- 0171-967X. ; 86:5, s. 359-366
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Tidskriftsartikel (refereegranskat)abstract
- Parathyroid hormone (PTH) is a principal regulator of calcium homeostasis. Previously, we studied single-nucleotide polymorphisms present in the major genes in the PTH pathway (PTH, PTHrP, PTHR1, PTHR2) in relation to bone mineral density (BMD) and fracture incidence. We found that haplotypes of the PTH gene were associated with fracture risk independent of BMD. In the present study, we evaluated the relationship between PTH haplotypes and femoral neck bone size. Hip structure analysis and BMD of the femoral neck was assessed by DXA in elderly women from the Malmö Osteoporosis Prospective Risk Assessment study. Data on hip fracture, sustained as a result of low trauma, after the age of 45 years were also analyzed. Haplotypes derived from six polymorphisms in the PTH locus were analyzed in 750 women. Carriers of haplotype 9 had lower values for hip geometry parameters cross-sectional moment of inertia (P = 0.029), femoral neck width (P = 0.049), and section modulous (P = 0.06), suggestive of increased fracture risk at the hip. However, this did not translate into an increased incidence of hip fracture in the studied population. Women who suffered a hip fracture compared to those who had not had longer hip axis length (HAL) (P < 0.001). HAL was not significantly different among haplotypes. Polymorphisms in the PTH gene are associated with differences in aspects of femoral neck geometry in elderly women; however, the major predictor of hip fracture in our population was HAL, to which PTH gene variation does not contribute significantly.
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| 65. |
- Uitterlinden, André G, et al.
(författare)
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The association between common vitamin D receptor gene variations and osteoporosis : a participant-level meta-analysis
- 2006
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Ingår i: Annals of Internal Medicine. - 0003-4819. ; 145:4, s. 255-264
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Polymorphisms of the vitamin D receptor (VDR) gene have been implicated in the genetic regulation of bone mineral density (BMD). However, the clinical impact of these variants remains unclear.OBJECTIVE: To evaluate the relation between VDR polymorphisms, BMD, and fractures.DESIGN: Prospective multicenter large-scale association study.SETTING: The Genetic Markers for Osteoporosis consortium, involving 9 European research teams.PARTICIPANTS: 26,242 participants (18,405 women).MEASUREMENTS: Cdx2 promoter, FokI, BsmI, ApaI, and TaqI polymorphisms; BMD at the femoral neck and the lumbar spine by dual x-ray absorptiometry; and fractures.RESULTS: Comparisons of BMD at the lumbar spine and femoral neck showed nonsignificant differences less than 0.011 g/cm2 for any genotype with or without adjustments. A total of 6067 participants reported a history of fracture, and 2088 had vertebral fractures. For all VDR alleles, odds ratios for fractures were very close to 1.00 (range, 0.98 to 1.02) and collectively the 95% CIs ranged from 0.94 (lowest) to 1.07 (highest). For vertebral fractures, we observed a 9% (95% CI, 0% to 18%; P = 0.039) risk reduction for the Cdx2 A-allele (13% risk reduction in a dominant model).LIMITATIONS: The authors analyzed only selected VDR polymorphisms. Heterogeneity was detected in some analyses and may reflect some differences in collection of fracture data across cohorts. Not all fractures were related to osteoporosis.CONCLUSIONS: The FokI, BsmI, ApaI, and TaqI VDR polymorphisms are not associated with BMD or with fractures, but the Cdx2 polymorphism may be associated with risk for vertebral fractures.
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| 66. |
- van Meurs, Joyce B, et al.
(författare)
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Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis.
- 2008
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Ingår i: JAMA : the journal of the American Medical Association. - Chicago : American Medical Association (AMA). - 1538-3598 .- 0098-7484. ; 299:11, s. 1277-90
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene cause rare syndromes characterized by altered bone mineral density (BMD). More common LRP5 variants may affect osteoporosis risk in the general population. OBJECTIVE: To generate large-scale evidence on whether 2 common variants of LRP5 (Val667Met, Ala1330Val) and 1 variant of LRP6 (Ile1062Val) are associated with BMD and fracture risk. DESIGN AND SETTING: Prospective, multicenter, collaborative study of individual-level data on 37,534 individuals from 18 participating teams in Europe and North America. Data were collected between September 2004 and January 2007; analysis of the collected data was performed between February and May 2007. Bone mineral density was assessed by dual-energy x-ray absorptiometry. Fractures were identified via questionnaire, medical records, or radiographic documentation; incident fracture data were available for some cohorts, ascertained via routine surveillance methods, including radiographic examination for vertebral fractures. MAIN OUTCOME MEASURES: Bone mineral density of the lumbar spine and femoral neck; prevalence of all fractures and vertebral fractures. RESULTS: The Met667 allele of LRP5 was associated with reduced lumbar spine BMD (n = 25,052 [number of participants with available data]; 20-mg/cm2 lower BMD per Met667 allele copy; P = 3.3 x 10(-8)), as was the Val1330 allele (n = 24,812; 14-mg/cm2 lower BMD per Val1330 copy; P = 2.6 x 10(-9)). Similar effects were observed for femoral neck BMD, with a decrease of 11 mg/cm2 (P = 3.8 x 10(-5)) and 8 mg/cm2 (P = 5.0 x 10(-6)) for the Met667 and Val1330 alleles, respectively (n = 25 193). Findings were consistent across studies for both LRP5 alleles. Both alleles were associated with vertebral fractures (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.08-1.47 for Met667 [2001 fractures among 20 488 individuals] and OR, 1.12; 95% CI, 1.01-1.24 for Val1330 [1988 fractures among 20,096 individuals]). Risk of all fractures was also increased with Met667 (OR, 1.14; 95% CI, 1.05-1.24 per allele [7876 fractures among 31,435 individuals)]) and Val1330 (OR, 1.06; 95% CI, 1.01-1.12 per allele [7802 fractures among 31 199 individuals]). Effects were similar when adjustments were made for age, weight, height, menopausal status, and use of hormone therapy. Fracture risks were partly attenuated by adjustment for BMD. Haplotype analysis indicated that Met667 and Val1330 variants both independently affected BMD. The LRP6 Ile1062Val polymorphism was not associated with any osteoporosis phenotype. All aforementioned associations except that between Val1330 and all fractures and vertebral fractures remained significant after multiple-comparison adjustments. CONCLUSIONS: Common LRP5 variants are consistently associated with BMD and fracture risk across different white populations. The magnitude of the effect is modest. LRP5 may be the first gene to reach a genome-wide significance level (a conservative level of significance [herein, unadjusted P < 10(-7)] that accounts for the many possible comparisons in the human genome) for a phenotype related to osteoporosis.
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| 67. |
- von Friesendorff, My, et al.
(författare)
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Hip fracture in men-survival and subsequent fractures: a cohort study with 22-year follow-up.
- 2011
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Ingår i: Journal of the American Geriatrics Society. - : Wiley. - 0002-8614. ; 59:5, s. 806-813
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Tidskriftsartikel (refereegranskat)abstract
- Abstract OBJECTIVES: To evaluate the influence of age on survival and risk of subsequent fracture in men with hip fracture, applying a residual lifetime perspective. DESIGN: Retrospective cohort study with 22-year follow-up. SETTING: Skåne University Hospital, Malmö, Sweden. PARTICIPANTS: Men aged 60 and older (N=226) with an index hip fracture during 1984/85. MEASUREMENTS: Twenty-two-year survival (mortality) and risk of new fractures evaluated in 5-year age bands and age groups (<75, 75-84, ≥85). RESULTS: Mean age was 78±9. Mortality at 22 years was 98%. Survivors were all younger than 75 at inclusion. Mortality was dependent on age at all time points (18%, 38%, 69% at 1 year, increasing to 71%, 93%, 100% by 10 years in <75, 75-84, ≥85, respectively). Median survival was 5.4 years, 2.0 years, and 3 months, respectively, in these age groups, and 33%, 27%, and 13% of each age-group sustained subsequent fractures, generally within 5 years. Overall 10-year fracture risk was 29% (95% confidence interval (CI)=19-38%), increasing to 44% (95% CI=30-58%) when adjusted for mortality. Residual lifetime risk of new fracture was 33% (95% CI=23-43%), and mortality-adjusted risk was 63% (95% CI=45-81%). Participants younger than 75 at index hip fracture were at greatest risk of new fracture (hazard ratio=2.7, 95% CI=1.1-6.4, P=.03). CONCLUSION: Almost one-third of men with hip fracture have subsequent fractures during their remaining lifetime. Time at risk is highly dependent on age. Most new fractures occur in relatively younger men and within 5 years, whereas most aged 75 and older die before experiencing a new fracture.
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| 68. |
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| 69. |
- Woolf, Anthony D., et al.
(författare)
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Clinical advances – from bench to bedside
- 2020
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Ingår i: Best Practice and Research: Clinical Rheumatology. - : Elsevier BV. - 1521-6942. ; 34:5
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Forskningsöversikt (refereegranskat)
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| 70. |
- Zheng, Hou-Feng, et al.
(författare)
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Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 526:7571, s. 112-
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Tidskriftsartikel (refereegranskat)abstract
- The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF <= 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants(1-8), as well as rare, population specific, coding variants(9). Here we identify novel non-coding genetic variants with large effects on BMD (n(total) = 53,236) and fracture (n(total) = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD8 (rs11692564(T), MAF51.6%, replication effect size510.20 s.d., P-meta = 2 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 x 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size +10.41 s.d., P-meta = 1 x 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.
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