| 1. |
- Grundberg, Elin, et al.
(författare)
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Population genomics in a disease targeted primary cell model
- 2009
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 19:11, s. 1942-1952
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Tidskriftsartikel (refereegranskat)abstract
- The common genetic variants associated with complex traits typically lie in noncoding DNA and may alter gene regulation in a cell type-specific manner. Consequently, the choice of tissue or cell model in the dissection of disease associations is important. We carried out an expression quantitative trait loci (eQTL) study of primary human osteoblasts (HOb) derived from 95 unrelated donors of Swedish origin, each represented by two independently derived primary lines to provide biological replication. We combined our data with publicly available information from a genome-wide association study (GWAS) of bone mineral density (BMD). The top 2000 BMD-associated SNPs (P < approximately 10(-3)) were tested for cis-association of gene expression in HObs and in lymphoblastoid cell lines (LCLs) using publicly available data and showed that HObs have a significantly greater enrichment (threefold) of converging cis-eQTLs as compared to LCLs. The top 10 BMD loci with SNPs showing strong cis-effects on gene expression in HObs (P = 6 x 10(-10) - 7 x 10(-16)) were selected for further validation using a staged design in two cohorts of Caucasian male subjects. All 10 variants were tested in the Swedish MrOS Cohort (n = 3014), providing evidence for two novel BMD loci (SRR and MSH3). These variants were then tested in the Rotterdam Study (n = 2090), yielding converging evidence for BMD association at the 17p13.3 SRR locus (P(combined) = 5.6 x 10(-5)). The cis-regulatory effect was further fine-mapped to the proximal promoter of the SRR gene (rs3744270, r(2) = 0.5, P = 2.6 x 10(-15)). Our results suggest that primary cells relevant to disease phenotypes complement traditional approaches for prioritization and validation of GWAS hits for follow-up studies.
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| 2. |
- Lewerin, Catharina, 1961, et al.
(författare)
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Low holotranscobalamin and cobalamins predict incident fractures in elderly men: the MrOS Sweden.
- 2014
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Ingår i: Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. - : Springer Science and Business Media LLC. - 1433-2965 .- 0937-941X. ; 25:1, s. 131-140
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Tidskriftsartikel (refereegranskat)abstract
- In a population-based study on cobalamin status and incident fractures in elderly men (n=790) with an average follow-up of 5.9years, we found that low levels of metabolically active and total cobalamins predict incident fractures, independently of body mass index (BMI), bone mineral density (BMD), plasma total homocysteine (tHcy), and cystatin C.
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| 3. |
- Kherad, Mehrsa, et al.
(författare)
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Risk factors for low back pain and sciatica in elderly men-the MrOS Sweden study
- 2017
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Ingår i: Age and Ageing. - : Oxford University Press (OUP). - 0002-0729 .- 1468-2834. ; 46:1, s. 64-71
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: the aim of this study was to identify whether factors beyond anatomical abnormalities are associated with low back pain (LBP) and LBP with sciatica (SCI) in older men. MATERIAL AND METHODS: Mister Osteoporosis Sweden includes 3,014 men aged 69-81 years. They answered questionnaires on lifestyle and whether they had experienced LBP and SCI during the preceding 12 months. About 3,007 men answered the back pain (BP) questions, 258 reported BP without specified region. We identified 1,388 with no BP, 1,361 with any LBP (regardless of SCI), 1,074 of those with LBP also indicated if they had experienced LBP (n = 615), LBP+SCI (n = 459). RESULTS: about 49% of those with LBP and 54% of those with LBP+SCI rated their health as poor/very poor (P < 0.001). Men with any LBP to a greater extent than those without BP had poor self-estimated health, depressive symptoms, dizziness, fall tendency, serious comorbidity (diabetes, stroke, coronary heart disease, pulmonary disease and/or cancer) (all P < 0.001), foreign background, were smokers (all P < 0.01), had low physical activity and used walking aids (all P < 0.05). Men with LBP+SCI to a greater extent than those with LBP had lower education, lower self-estimated health, comorbidity, dizziness and used walking aids (all P < 0.001). CONCLUSIONS: in older men with LBP and SCI, anatomical abnormalities such as vertebral fractures, metastases, central or lateral spinal stenosis or degenerative conditions may only in part explain prevalent symptoms and disability. Social and lifestyle factors must also be evaluated since they are associated not only with unspecific LBP but also with LBP with SCI.
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| 4. |
- 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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| 5. |
- Cöster, Marcus E., et al.
(författare)
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Physical function tests predict incident falls : A prospective study of 2969 men in the Swedish Osteoporotic Fractures in Men study
- 2020
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Ingår i: Scandinavian Journal of Public Health. - : SAGE Publications. - 1403-4948 .- 1651-1905. ; 48:4, s. 436-441
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Falls are common in the elderly population, and fall-related injuries are a major health issue. We investigated the ability of simple physical tests to predict incident falls. Methods: The Swedish Osteoporotic Fractures in Men (MrOS) study includes 3014 population-based men aged 69–81 years at the start of the study. These men performed five different physical tests at baseline: right-hand grip strength, left-hand grip strength, timed stand test, 6 m walking test (time and steps) and narrow walking test. During the first study year, we asked participants to fill out questionnaires regarding falls 4, 8 and 12 months after baseline. A total of 2969 men completed at least one questionnaire and were included in this study. We used generalised estimating equations and logarithmic regression models to estimate odds ratios for fallers and recurrent fallers (more than one fall during the one-year examination period) in each quartile of men for each physical test. Results: The proportions of fallers and recurrent fallers were higher in the lowest quartile of the physical tests than in the other three quartiles combined for all physical tests. A reduction of one standard deviation in respective physical test resulted in a 13–21% higher risk of becoming a faller and a 13–31% higher risk of becoming a recurrent faller. Conclusions: Low results on simple physical tests is a risk factor for incident falls in elderly Swedish men and may facilitate identification of high-risk individuals suitable for fall-intervention programs.
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| 6. |
- Jutberger, Hans, et al.
(författare)
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Smoking Predicts Incident Fractures in Elderly Men : Mr OS Sweden
- 2010
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Ingår i: Journal of Bone and Mineral Research. - : Wiley. - 0884-0431 .- 1523-4681. ; 25:5, s. 1010-1016
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the present study was to investigate the association between smoking and BMD, radiographically verified prevalent vertebral fractures and incident fractures in elderly men. At baseline 3003 men, aged 69 - 80 years old from the Swedish Mr Os study, completed a standard questionnaire concerning smoking habits and had BMD of the hip and spine measured using DXA; 1412 men had an X-ray of the thoracic-/lumbar spine. Radiological registers were used to confirm reported new fractures after the baseline visit. At baseline 8.4 % were current smokers. Current smokers had 6.2 % lower BMD at the total hip and 5.4 % at the lumbar spine (p<0.001). Current smoking remained independently, inversely associated with BMD at the hip and lumbar spine after adjusting for age, height, weight, calcium intake, physical activity and centres as co-variates. Prevalent vertebral fractures among current smokers were increased in unadjusted analyses (OR 1.90; 95% CI: 1.26-2.87) and after adjustment for lumbar BMD (OR 1.67; 1.09-2.55). Smokers had a high risk for two or more prevalent vertebral fractures (OR 3.18; 1.88-5.36). During the average follow-up of 3.3 years, 209 men sustained an X-ray verified fracture. Incident fracture risk among smokers was calculated with Cox proportional hazard models. Current smokers had increased risk of all new fractures (HR 1.76; 1.19-2.61), non-vertebral osteoporotic fractures defined as humerus, radius, pelvis and hip fractures (HR 2.14; 1.18-3.88), clinical and X-ray verified vertebral fractures (HR 2.53; 1.37-4.65) as well as of hip fracture (HR 3.16; 1.44-6.95). After adjustment for BMD, including other co-variates, no significant association between smoking and incident fractures was found. Current tobacco smoking in elderly men is associated with low BMD, prevalent vertebral fractures and incident fractures, especially vertebral and hip fractures.
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| 7. |
- Almqvist, Erik G., et al.
(författare)
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Factors influencing insulin sensitivity in patients with mild primary hyperparathyroidism before and after parathyroidectomy
- 2012
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Ingår i: Scandinavian Journal of Clinical & Laboratory Investigation. - : Informa UK Limited. - 1502-7686 .- 0036-5513. ; 72:2, s. 92-99
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Tidskriftsartikel (refereegranskat)abstract
- Objectives. Primary hyperparathyroidism (PHPT) is associated with cardiovascular disease. The aims of this study were to investigate lipid and glucose metabolism in mild PHPT, and to identify whether insulin sensitivity correlates with circulating levels of adiponectin, SHBG, and osteocalcin before and after parathyroidectomy (PTX). Materials and methods. Forty-five patients with PHPT were examined before and 1 year after PTX. Circulating levels of triglycerides, total cholesterol, HDL-cholesterol, insulin, glucose, adiponectin, SHBG, osteocalcin, and erythropoietin were measured. Results. At baseline, the mean serum levels of total cholesterol, LDL-cholesterol and triglycerides were above the upper reference limit or in the upper normal range, and insulin sensitivity was reduced as assessed using the HOMA index. One year after parathyroidectomy, serum lipids as well as HOMA index and erythropoietin were unchanged while adiponectin had increased (p < 0.05), and SHBG and osteocalcin had decreased (p < 0.05 and p < 0.0001, respectively). HOMA index correlated negatively with circulating levels of adiponectin, SHBG and osteocalcin. In multiple regression analysis SHBG was the most important predictor of insulin sensitivity, both pre- and postoperatively. Conclusion. Untreated mild PHPT is associated with a moderate derangement of lipid and glucose metabolism. As previously shown in population-based cohorts, insulin sensitivity is positively associated with circulating concentrations of adiponectin, SHBG and osteocalcin. One year after PTX, the mean level of adiponectin was increased, but the levels of SHBG and osteocalcin had decreased and the levels of serum lipids and the insulin sensitivity remained unchanged as compared with baseline.
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| 8. |
- Yeap, B. B., et al.
(författare)
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Androgens in men study (AIMS): Protocol for meta-analyses of individual participant data investigating associations of androgens with health outcomes in men
- 2020
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Ingår i: BMJ Open. - : BMJ. - 2044-6055. ; 10:5
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Tidskriftsartikel (refereegranskat)abstract
- Introduction This study aims to clarify the role(s) of endogenous sex hormones to influence health outcomes in men, specifically to define the associations of plasma testosterone with incidence of cardiovascular events, cancer, dementia and mortality risk, and to identify factors predicting testosterone concentrations. Data will be accrued from at least three Australian, two European and four North American population-based cohorts involving approximately 20 000 men. Methods and analysis Eligible studies include prospective cohort studies with baseline testosterone concentrations measured using mass spectrometry and 5 years of follow-up data on incident cardiovascular events, mortality, cancer diagnoses or deaths, new-onset dementia or decline in cognitive function recorded. Data for men, who were not taking androgens or drugs suppressing testosterone production, metabolism or action; and had no prior orchidectomy, are eligible. Systematic literature searches were conducted from 14 June 2019 to 31 December 2019, with no date range set for searches. Aggregate level data will be sought where individual participant data (IPD) are not available. One-stage IPD random-effects meta-analyses will be performed, using linear mixed models, generalised linear mixed models and either stratified or frailty-augmented Cox regression models. Heterogeneity in estimates from different studies will be quantified and bias investigated using funnel plots. Effect size estimates will be presented in forest plots and non-negligible heterogeneity and bias investigated using subgroup or meta-regression analyses. Ethics and dissemination Ethics approvals obtained for each of the participating cohorts state that participants have consented to have their data collected and used for research purposes. The Androgens In Men Study has been assessed as exempt from ethics review by the Human Ethics office at the University of Western Australia (file reference number RA/4/20/5014). Each of the component studies had obtained ethics approvals; please refer to respective component studies for details. Research findings will be disseminated to the scientific and broader community via the publication of four research articles, with each involving a separate set of IPD meta-analyses (articles will investigate different, distinct outcomes), at scientific conferences and meetings of relevant professional societies. Collaborating cohort studies will disseminate findings to study participants and local communities. PROSPERO registration number CRD42019139668. © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.
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| 9. |
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| 10. |
- Zheng, Hou-Feng, et al.
(författare)
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WNT16 influences bone mineral density, Cortical bone thickness, bone strength, and Osteoporotic fracture risk
- 2012
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Ingår i: PLoS genetics. - SAN FRANCISCO, USA : PUBLIC LIBRARY SCIENCE. - 1553-7404. ; 8:7, s. e1002745-
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Tidskriftsartikel (refereegranskat)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)
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