| 1. |
- Johannesdottir, Fjola, et al.
(författare)
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Distribution of cortical bone in the femoral neck and hip fracture: A prospective case-control analysis of 143 incident hip fractures; the AGES-REYKJAVIK Study
- 2011
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Ingår i: Bone. - : Elsevier BV. - 1873-2763 .- 8756-3282. ; 48:6, s. 1268-1276
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Tidskriftsartikel (refereegranskat)abstract
- In this prospective nested case-control study we analyzed the circumferential differences in estimated cortical thickness (Est CTh) of the mid femoral neck as a risk factor for osteoporotic hip fractures in elderly women and men. Segmental QCT analysis of the mid femoral neck was applied to assess cortical thickness in anatomical quadrants. The superior region of the femoral neck was a stronger predictor for hip fracture than the inferior region, particularly in men. There were significant gender differences in Est CTh measurements in the control group but not in the case group. In multivariable analysis for risk of femoral neck (FN) fracture, Est CTh in the supero-anterior (SA) quadrant was significant in both women and men, and remained a significant predictor after adjustment for FN areal BMD (aBMD, dimensions g/cm(2), DXA-like), (p = 0.05 and p<0.0001, respectively). In conclusion, Est CTh in the SA quadrant best discriminated cases (n = 143) from controls (n = 298), especially in men. Cortical thinning superiorly in the hip might be of importance in determining resistance to fracture. (C) 2011 Elsevier Inc. All rights reserved.
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| 2. |
- Johannesdottir, Fjola, et al.
(författare)
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Mid-Thigh Cortical Bone Structural Parameters, Muscle Mass and Strength, and Association with Lower Limb Fractures in Older Men and Women (AGES-Reykjavik Study)
- 2012
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Ingår i: Calcified Tissue International. - : Springer Science and Business Media LLC. - 1432-0827 .- 0171-967X. ; 90:5, s. 354-364
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Tidskriftsartikel (refereegranskat)abstract
- In a cross-sectional study we investigated the relationship between muscle and bone parameters in the mid-thigh in older people using data from a single axial computed tomographic section through the mid-thigh. Additionally, we studied the association of these variables with incident low-trauma lower limb fractures. A total of 3,762 older individuals (1,838 men and 1,924 women), aged 66-96 years, participants in the AGES-Reykjavik study, were studied. The total cross-sectional muscular area and knee extensor strength declined with age similarly in both sexes. Muscle parameters correlated most strongly with cortical area and total shaft area (adjusted for age, height, and weight) but explained < 10 % of variability in those bone parameters. The increment in medullary area (MA) and buckling ratio (BR) with age was almost fourfold greater in women than men. The association between MA and muscle parameters was nonsignificant. During a median follow-up of 5.3 years, 113 women and 66 men sustained incident lower limb fractures. Small muscular area, low knee extensor strength, large MA, low cortical thickness, and high BR were significantly associated with fractures in both sexes. Our results show that bone and muscle loss proceed at different rates and with different gender patterns.
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| 3. |
- Rianon, Nahid J., et al.
(författare)
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Fracture Risk Assessment in Older Adults Using a Combination of Selected Quantitative Computed Tomography Bone Measures: A Subanalysis of the Age, Gene/Environment Susceptibility-Reykjavik Study
- 2014
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Ingår i: Journal of Clinical Densitometry. - : Elsevier BV. - 1094-6950. ; 17:1, s. 25-31
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Tidskriftsartikel (refereegranskat)abstract
- Bone mineral density (BMD) and geometric bone measures are individually associated with prevalent osteoporotic fractures. Whether an aggregate of these measures would better associate with fractures has not been examined. We examined relationships between self-reported fractures and selected bone measures acquired by quantitative computerized tomography (QCT), a composite bone score, and QCT-acquired dual-energy X-ray absorptiometry-like total femur BMD in 2110 men and 2682 women in the Age, Gene/Environment Susceptibility-Reykjavik Study. The combined bone score was generated by summing gender-specific Z-scores for 4 QCT measures: vertebral trabecular BMD, femur neck cortical thickness, femur neck trabecular BMD, and femur neck minimal cross-sectional area. Except for the latter measure, lower scores for QCT measures, singly and combined, showed positive (p < 0.05) associations with fractures. Results remained the same in stratified models for participants not taking bone-promoting medication. In women on bone-promoting medication, greater femur neck cortical thickness and trabecular BMD were significantly associated with fracture status. However, the association between fracture and combined bone score was not stronger than the associations between fracture and individual measures or total femur BMD. Thus, the selected measures did not all similarly associate with fracture status and did not appear to have an additive effect on fracture status.
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| 4. |
- Sandling, Johanna K., et al.
(författare)
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A candidate gene study of the type I interferon pathway implicates IKBKE and IL8 as risk loci for SLE
- 2011
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 19:4, s. 479-484
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Tidskriftsartikel (refereegranskat)abstract
- Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease in which the type I interferon pathway has a crucial role. We have previously shown that three genes in this pathway, IRF5, TYK2 and STAT4, are strongly associated with risk for SLE. Here, we investigated 78 genes involved in the type I interferon pathway to identify additional SLE susceptibility loci. First, we genotyped 896 single-nucleotide polymorphisms in these 78 genes and 14 other candidate genes in 482 Swedish SLE patients and 536 controls. Genes with P<0.01 in the initial screen were then followed up in 344 additional Swedish patients and 1299 controls. SNPs in the IKBKE, TANK, STAT1, IL8 and TRAF6 genes gave nominal signals of association with SLE in this extended Swedish cohort. To replicate these findings we extracted data from a genomewide association study on SLE performed in a US cohort. Combined analysis of the Swedish and US data, comprising a total of 2136 cases and 9694 controls, implicates IKBKE and IL8 as SLE susceptibility loci (P(meta)=0.00010 and P(meta)=0.00040, respectively). STAT1 was also associated with SLE in this cohort (P(meta)=3.3 × 10(-5)), but this association signal appears to be dependent of that previously reported for the neighbouring STAT4 gene. Our study suggests additional genes from the type I interferon system in SLE, and highlights genes in this pathway for further functional analysis.
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| 5. |
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| 6. |
- Sigurdsson, Snaevar, et al.
(författare)
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A risk haplotype of STAT4 for systemic lupus erythematosus is over-expressed, correlates with anti-dsDNA and shows additive effects with two risk alleles of IRF5
- 2008
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 17:18, s. 2868-2876
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Tidskriftsartikel (refereegranskat)abstract
- Systemic lupus erythematosus (SLE) is the prototype autoimmune disease where genes regulated by type I interferon (IFN) are over-expressed and contribute to the disease pathogenesis. Because signal transducer and activator of transcription 4 (STAT4) plays a key role in the type I IFN receptor signaling, we performed a candidate gene study of a comprehensive set of single nucleotide polymorphism (SNPs) in STAT4 in Swedish patients with SLE. We found that 10 out of 53 analyzed SNPs in STAT4 were associated with SLE, with the strongest signal of association (P = 7.1 x 10(-8)) for two perfectly linked SNPs rs10181656 and rs7582694. The risk alleles of these 10 SNPs form a common risk haplotype for SLE (P = 1.7 x 10(-5)). According to conditional logistic regression analysis the SNP rs10181656 or rs7582694 accounts for all of the observed association signal. By quantitative analysis of the allelic expression of STAT4 we found that the risk allele of STAT4 was over-expressed in primary human cells of mesenchymal origin, but not in B-cells, and that the risk allele of STAT4 was over-expressed (P = 8.4 x 10(-5)) in cells carrying the risk haplotype for SLE compared with cells with a non-risk haplotype. The risk allele of the SNP rs7582694 in STAT4 correlated to production of anti-dsDNA (double-stranded DNA) antibodies and displayed a multiplicatively increased, 1.82-fold risk of SLE with two independent risk alleles of the IRF5 (interferon regulatory factor 5) gene.
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| 7. |
- Sigurdsson, Snaevar, et al.
(författare)
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Comprehensive evaluation of the genetic variants of interferon regulatory factor 5 (IRF5) reveals a novel 5 bp length polymorphism as strong risk factor for systemic lupus erythematosus
- 2008
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 17:6, s. 872-881
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Tidskriftsartikel (refereegranskat)abstract
- We analyzed a comprehensive set of single-nucleotide polymorphisms (SNPs) and length polymorphisms in the interferon regulatory factor 5 (IRF5) gene for their association with the autoimmune disease systemic lupus erythematosus (SLE) in 485 Swedish patients and 563 controls. We found 16 SNPs and two length polymorphisms that display association with SLE (P < 0.0005, OR > 1.4). Using a Bayesian model selection and averaging approach we identified parsimonious models with exactly two variants of IRF5 that are independently associated with SLE. The variants of IRF5 with the highest posterior probabilities (1.00 and 0.71, respectively) of being causal in SLE are a SNP (rs10488631) located 3' of IRF5, and a novel CGGGG insertion-deletion (indel) polymorphism located 64 bp upstream of the first untranslated exon (exon 1A) of IRF5. The CGGGG indel explains the association signal from multiple SNPs in the IRF5 gene, including rs2004640, rs10954213 and rs729302 previously considered to be causal variants in SLE. The CGGGG indel contains three or four repeats of the sequence CGGGG with the longer allele containing an additional SP1 binding site as the risk allele for SLE. Using electrophoretic mobility shift assays we show increased binding of protein to the risk allele of the CGGGG indel and using a minigene reporter assay we show increased expression of IRF5 mRNA from a promoter containing this allele. Increased expression of IRF5 protein was observed in peripheral blood mononuclear cells from SLE patients carrying the risk allele of the CGGGG indel. We have found that the same IRF5 allele also confers risk for inflammatory bowel diseases and multiple sclerosis, suggesting a general role for IRF5 in autoimmune diseases.
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| 8. |
- Estrada, Karol, et al.
(författare)
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Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.
- 2012
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:5, s. 491-501
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Tidskriftsartikel (refereegranskat)abstract
- Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.
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| 9. |
- Feng, Di, et al.
(författare)
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Genetic variants and disease-associated factors contribute to enhanced interferon regulatory factor 5 expression in blood cells of patients with systemic lupus erythematosus
- 2010
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 62:2, s. 562-573
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Genetic variants of the interferon (IFN) regulatory factor 5 gene (IRF5) are associated with susceptibility to systemic lupus erythematosus (SLE). The contribution of these variants to IRF-5 expression in primary blood cells of SLE patients has not been addressed, nor has the role of type I IFNs. The aim of this study was to determine the association between increased IRF-5 expression and the IRF5 risk haplotype in SLE patients. METHODS: IRF-5 transcript and protein levels in 44 Swedish patients with SLE and 16 healthy controls were measured by quantitative real-time polymerase chain reaction, minigene assay, and flow cytometry. Single-nucleotide polymorphisms rs2004640, rs10954213, and rs10488631 and the CGGGG insertion/deletion were genotyped in these patients. Genotypes of these polymorphisms defined both a common risk haplotype and a common protective haplotype. RESULTS: IRF-5 expression and alternative splicing were significantly up-regulated in SLE patients compared with healthy donors. Enhanced transcript and protein levels were associated with the risk haplotype of IRF5; rs10488631 displayed the only significant independent association that correlated with increased transcription from the noncoding first exon 1C. Minigene experiments demonstrated an important role for rs2004640 and the CGGGG insertion/deletion, along with type I IFNs, in regulating IRF5 expression. CONCLUSION: This study provides the first formal proof that IRF-5 expression and alternative splicing are significantly up-regulated in primary blood cells of patients with SLE. Furthermore, the risk haplotype is associated with enhanced IRF-5 transcript and protein expression in patients with SLE.
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| 10. |
- Gaulton, Kyle J, et al.
(författare)
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Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.
- 2015
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:12, s. 1415-1415
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Tidskriftsartikel (refereegranskat)abstract
- We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
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| 11. |
- Helgadottir, Anna, et al.
(författare)
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The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm
- 2008
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 40:2, s. 217-224
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Tidskriftsartikel (refereegranskat)abstract
- Recently, two common sequence variants on 9p21, tagged by rs10757278-G and rs10811661-T, were reported to be associated with coronary artery disease (CAD)(1-4) and type 2 diabetes (T2D)(5-7), respectively. We proceeded to further investigate the contributions of these variants to arterial diseases and T2D. Here we report that rs10757278-G is associated with, in addition to CAD, abdominal aortic aneurysm (AAA; odds ratio (OR) 1.31, P = 1.2 x 10(-12)) and intracranial aneurysm (OR = 1.29, P = 2.5 x 10(-6)), but not with T2D. This variant is the first to be described that affects the risk of AAA and intracranial aneurysm in many populations. The association of rs10811661-T to T2D replicates in our samples, but the variant does not associate with any of the five arterial diseases examined. These findings extend our insight into the role of the sequence variant tagged by rs10757278-G and show that it is not confined to atherosclerotic diseases.
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| 12. |
- Kiemeney, Lambertus A, et al.
(författare)
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A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer.
- 2010
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 42:5, s. 415-9
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Tidskriftsartikel (refereegranskat)abstract
- Previously, we reported germline DNA variants associated with risk of urinary bladder cancer (UBC) in Dutch and Icelandic subjects. Here we expanded the Icelandic sample set and tested the top 20 markers from the combined analysis in several European case-control sample sets, with a total of 4,739 cases and 45,549 controls. The T allele of rs798766 on 4p16.3 was found to associate with UBC (odds ratio = 1.24, P = 9.9 x 10(-12)). rs798766 is located in an intron of TACC3, 70 kb from FGFR3, which often harbors activating somatic mutations in low-grade, noninvasive UBC. Notably, rs798766[T] shows stronger association with low-grade and low-stage UBC than with more aggressive forms of the disease and is associated with higher risk of recurrence in low-grade stage Ta tumors. The frequency of rs798766[T] is higher in Ta tumors that carry an activating mutation in FGFR3 than in Ta tumors with wild-type FGFR3. Our results show a link between germline variants, somatic mutations of FGFR3 and risk of UBC.
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| 13. |
- Kilpeläinen, Tuomas O, et al.
(författare)
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Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile.
- 2011
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:8, s. 753-60
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between ∼2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10(-6)) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 × 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 × 10(-11)) and one near SPRY2 (P = 3 × 10(-8)). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance.
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| 14. |
- Kvale, Reidar, et al.
(författare)
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The Nordic perioperative and intensive care registries-Collaboration and research possibilities
- 2023
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Ingår i: Acta Anaesthesiologica Scandinavica. - : WILEY. - 0001-5172 .- 1399-6576. ; 67:7, s. 972-978
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Tidskriftsartikel (refereegranskat)abstract
- Background: The Nordic perioperative and intensive care registries have been built up during the last 25 years to improve quality in intensive and perioperative care. We aimed to describe the Nordic perioperative and intensive care registries and to highlight possibilities and challenges in future research collaboration between these registries.Material and method: We present an overview of the following Nordic registries: Swedish Perioperative Registry (SPOR), the Danish Anesthesia Database (DAD), the Finnish Perioperative Database (FIN-AN), the Icelandic Anesthesia Database (IS-AN), the Danish Intensive Care Database (DID), the Swedish Intensive Care Registry (SIR), the Finnish Intensive Care Consortium, the Norwegian Intensive Care and Pandemic Registry (NIPaR), and the Icelandic Intensive Care Registry (IS-ICU).Results: Health care systems and patient populations are similar in the Nordic countries. Despite certain differences in data structure and clinical variables, the perioperative and intensive care registries have enough in common to enable research collaboration. In the future, even a common Nordic registry could be possible.Conclusion: Collaboration between the Nordic perioperative and intensive care registries is both possible and likely to produce research of high quality. Research collaboration between registries may have several add-on effects and stimulate international standardization regarding definitions, scoring systems, and benchmarks, thereby improving overall quality of care.
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| 15. |
- Larsson, Daniel, et al.
(författare)
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On some almost quadratic algebras coming from twisted derivations
- 2006
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Ingår i: Journal of Nonlinear Mathematical Physics. - 1402-9251 .- 1776-0852. ; 13, s. 76-86
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Tidskriftsartikel (refereegranskat)abstract
- This paper explores the quasi-deformation scheme devised in [1, 3] as applied to the simple Lie algebra sl(2)(F) for specific choices of the involved parameters and underlying algebras. One of the main points of this method is that the quasi-deformed algebra comes endowed with a canonical twisted Jacobi identity. We show in the present article that when the quasi-deformation method is applied to sl(2)(F) one obtains multiparameter families of almost quadratic algebras, and by choosing parameters suitably, sl(2)(F) is quasi-deformed into three-dimensional and four-dimensional Lie algebras and algebras closely resembling Lie superalgebras and colour Lie algebras, this being in stark contrast to the classical deformation schemes where sl(2)(F) is rigid.
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| 16. |
- Larsson, Daniel, et al.
(författare)
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On some almost quadratic algebras coming from twisted derivations
- 2006
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Ingår i: Journal of Nonlinear Mathematical Physics. - : Springer Science and Business Media LLC. - 1402-9251 .- 1776-0852. ; 13, s. 76-86
-
Tidskriftsartikel (refereegranskat)abstract
- This paper explores the quasi-deformation scheme devised in [1, 3] as applied to the simple Lie algebra sl(2)(F) for specific choices of the involved parameters and underlying algebras. One of the main points of this method is that the quasi-deformed algebra comes endowed with a canonical twisted Jacobi identity. We show in the present article that when the quasi-deformation method is applied to sl(2)(F) one obtains multiparameter families of almost quadratic algebras, and by choosing parameters suitably, sl(2)(F) is quasi-deformed into three-dimensional and four-dimensional Lie algebras and algebras closely resembling Lie superalgebras and colour Lie algebras, this being in stark contrast to the classical deformation schemes where sl(2)(F) is rigid.
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| 17. |
- Larsson, Daniel, et al.
(författare)
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Quasi-Lie deformations on the algebra F[t]/(tn)
- 2008
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Ingår i: Journal of Generalized Lie Theory and Applications. - 1736-5279 .- 1736-4337. ; 2:3, s. 201-205
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Tidskriftsartikel (refereegranskat)abstract
- This paper explores the quasi-deformation scheme devised by Hartwig, Larsson and Silvestrov as applied to the simple Lie algebra sl2(F). One of the main points of this method is that the quasi-deformed algebra comes endowed with a canonical twisted Jacobi identity. We show in the present article that when the quasi-deformation method is applied to sl2(F) via representations by twisted derivations on the algebra F[t]/(tN) one obtains interesting new multi-parameter families of almost quadratic algebras.
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| 18. |
- Liu, Ching-Ti, et al.
(författare)
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Assessment of gene-by-sex interaction effect on bone mineral density
- 2012
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Ingår i: Journal of Bone and Mineral Research. - : Wiley. - 1523-4681 .- 0884-0431. ; 27:10, s. 2051-2064
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Tidskriftsartikel (refereegranskat)abstract
- Sexual dimorphism in various bone phenotypes, including bone mineral density (BMD), is widely observed; however, the extent to which genes explain these sex differences is unclear. To identify variants with different effects by sex, we examined gene-by-sex autosomal interactions genome-wide, and performed expression quantitative trait loci (eQTL) analysis and bioinformatics network analysis. We conducted an autosomal genome-wide meta-analysis of gene-by-sex interaction on lumbar spine (LS) and femoral neck (FN) BMD in 25,353 individuals from 8 cohorts. In a second stage, we followed up the 12 top single-nucleotide polymorphisms (SNPs; p?
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| 19. |
- Oei, Ling, et al.
(författare)
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A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus
- 2014
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Ingår i: Journal of Medical Genetics. - : BMJ Publishing Group. - 0022-2593 .- 1468-6244. ; 51:2, s. 122-131
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Osteoporosis is a systemic skeletal disease characterised by reduced bone mineral density and increased susceptibility to fracture; these traits are highly heritable. Both common and rare copy number variants (CNVs) potentially affect the function of genes and may influence disease risk.AIM: To identify CNVs associated with osteoporotic bone fracture risk.METHOD: We performed a genome-wide CNV association study in 5178 individuals from a prospective cohort in the Netherlands, including 809 osteoporotic fracture cases, and performed in silico lookups and de novo genotyping to replicate in several independent studies.RESULTS: A rare (population prevalence 0.14%, 95% CI 0.03% to 0.24%) 210 kb deletion located on chromosome 6p25.1 was associated with the risk of fracture (OR 32.58, 95% CI 3.95 to 1488.89; p=8.69×10(-5)). We performed an in silico meta-analysis in four studies with CNV microarray data and the association with fracture risk was replicated (OR 3.11, 95% CI 1.01 to 8.22; p=0.02). The prevalence of this deletion showed geographic diversity, being absent in additional samples from Australia, Canada, Poland, Iceland, Denmark, and Sweden, but present in the Netherlands (0.34%), Spain (0.33%), USA (0.23%), England (0.15%), Scotland (0.10%), and Ireland (0.06%), with insufficient evidence for association with fracture risk.CONCLUSIONS: These results suggest that deletions in the 6p25.1 locus may predispose to higher risk of fracture in a subset of populations of European origin; larger and geographically restricted studies will be needed to confirm this regional association. This is a first step towards the evaluation of the role of rare CNVs in osteoporosis.
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| 20. |
- Palmer, Nicholette D, et al.
(författare)
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A genome-wide association search for type 2 diabetes genes in African Americans.
- 2012
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Ingår i: PloS one. - San Francisco : Public Library of Science (PLoS). - 1932-6203. ; 7:1, s. e29202-
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Tidskriftsartikel (refereegranskat)abstract
- African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
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| 21. |
- Perry, John R. B., et al.
(författare)
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Stratifying Type 2 Diabetes Cases by BMI Identifies Genetic Risk Variants in LAMA1 and Enrichment for Risk Variants in Lean Compared to Obese Cases
- 2012
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 8:5
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Tidskriftsartikel (refereegranskat)abstract
- Common diseases such as type 2 diabetes are phenotypically heterogeneous. Obesity is a major risk factor for type 2 diabetes, but patients vary appreciably in body mass index. We hypothesized that the genetic predisposition to the disease may be different in lean (BMI<25 Kg/m(2)) compared to obese cases (BMI >= 30 Kg/m(2)). We performed two case-control genome-wide studies using two accepted cut-offs for defining individuals as overweight or obese. We used 2,112 lean type 2 diabetes cases (BMI<25 kg/m(2)) or 4,123 obese cases (BMI >= 30 kg/m(2)), and 54,412 un-stratified controls. Replication was performed in 2,881 lean cases or 8,702 obese cases, and 18,957 un-stratified controls. To assess the effects of known signals, we tested the individual and combined effects of SNPs representing 36 type 2 diabetes loci. After combining data from discovery and replication datasets, we identified two signals not previously reported in Europeans. A variant (rs8090011) in the LAMA1 gene was associated with type 2 diabetes in lean cases (P = 8.4610 29, OR = 1.13 [95% CI 1.09-1.18]), and this association was stronger than that in obese cases (P = 0.04, OR = 1.03 [95% CI 1.00-1.06]). A variant in HMG20A-previously identified in South Asians but not Europeans-was associated with type 2 diabetes in obese cases (P = 1.3 x 10(-8), OR= 1.11 [95% CI 1.07-1.15]), although this association was not significantly stronger than that in lean cases (P = 0.02, OR = 1.09 [95% CI 1.02-1.17]). For 36 known type 2 diabetes loci, 29 had a larger odds ratio in the lean compared to obese (binomial P = 0.0002). In the lean analysis, we observed a weighted per-risk allele OR = 1.13 [95% CI 1.10-1.17], P = 3.2 x 10(-14). This was larger than the same model fitted in the obese analysis where the OR = 1.06 [95% CI 1.05-1.08], P = 2.2 x 10(-16). This study provides evidence that stratification of type 2 diabetes cases by BMI may help identify additional risk variants and that lean cases may have a stronger genetic predisposition to type 2 diabetes.
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| 22. |
- Scott, Robert A., et al.
(författare)
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An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans
- 2017
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 66:11, s. 2888-2902
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Tidskriftsartikel (refereegranskat)abstract
- To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 x 10(-8)), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.
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| 23. |
- Siggeirsdottir, Kristin, et al.
(författare)
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Effect of vertebral fractures on function, quality of life and hospitalisation the AGES-Reykjavik study
- 2012
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Ingår i: Age and Ageing. - : Oxford University Press (OUP). - 1468-2834 .- 0002-0729. ; 41:3, s. 351-357
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Tidskriftsartikel (refereegranskat)abstract
- Objective: assess the effect of clinical vertebral and other osteoporotic fractures on function and the subsequent risk of hospitalisation. Design: individuals from the prospective population-based cohort study Age, Gene/Environment Susceptibility (AGES)-Reykjavik study were examined between 2002 and 2006 and followed up for 5.4 years. Subjects: a total of 5,764 individuals, 57.7% women, born 1907-35, mean age 77. Method: four groups with a verified fracture status were used; vertebral fractures, other osteoporotic fractures excluding vertebral, non-osteoporotic fractures and not-fractured were compared and analysed for the effect on mobility, strength, QoL, ADL, co-morbidity and hospitalisation. Results: worst performance on functional tests was in the vertebral fracture group for women (P < 0.0001) and the other osteoporotic fractures group for men (P < 0.05). Both vertebral and other osteoporotic fractures, showed an increased risk of hospitalisation, HR = 1.4 (95% CI: 1.3-1.7) and 1.2 (95% CI: 1.1-1.2) respectively (P < 0.0001). Individuals with vertebral fractures had 50% (P < 0.0001) longer hospitalisation than not-fractured and 33% (P < 0.002) longer than the other osteoporotic fractures group. Conclusion: individuals with a history of clinical vertebral fracture seem to carry the greatest health burden compared with other fracture groups, emphasising the attention which should be given to those individuals.
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| 24. |
- Siggeirsdottir, Kristin, et al.
(författare)
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Inaccuracy in self-report of fractures may underestimate association with health outcomes when compared with medical record based fracture registry
- 2007
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Ingår i: European Journal of Epidemiology. - : Springer Science and Business Media LLC. - 1573-7284 .- 0393-2990. ; 22:9, s. 631-639
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Tidskriftsartikel (refereegranskat)abstract
- Introduction and objective Misreporting fractures in questionnaires is known. However, the effect of misreporting on the association of fractures with subsequent health outcomes has not been examined. Methods Data from a fracture registry (FR) developed from an extensive review of radiographic and medical records were related to self-report of fracture for 2,255 participants from the AGES Reykjavik Study. This data was used to determine false negative and false positive rates of self-reported fractures, correlates of misreporting, and the potential effect of the misreporting on estimates of health outcomes following fractures. Results In women, the false positive rate decreased with age as the false negative rate increased with no clear trend with age in men. Kappa values for agreement between FR and self-report were generally higher in women than men with the best agreement for forearm fracture (men 0.64 and women 0.82) and the least for rib (men 0.28 and women 0.25). Impaired cognition was a major factor associated with discordant answers between FR and self-report, OR 1.7 (95% CI: 1.3-2.1) (P < 0.0001). We estimated the effect of misreporting on health after fracture by comparison of the association of the self-report of fracture and fracture from the FR, adjusting for those factors associated with discordance. The weighted attenuation factor measured by mobility and muscle strength was 11% (95% CI: 0-24%) when adjusted for age and sex but reduced to 6% (95% CI: -10-22%) when adjusted for cognitive impairment. Conclusion Studies of hip fractures should include an independent ascertainment of fracture but for other fractures this study supports the use of self-report.
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| 25. |
- Sigurdsson, Gunnar, et al.
(författare)
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Bosonic realizations of the colour Heisenberg Lie algebra
- 2006
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Ingår i: Journal of Nonlinear Mathematical Physics. - : Springer Science and Business Media LLC. - 1402-9251 .- 1776-0852. ; 13, s. 110-128
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Tidskriftsartikel (refereegranskat)abstract
- We describe realizations of the colour analogue of the Heisenberg Lie algebra by power series in non-commuting indeterminates satisfying Heisenberg's canonical commutation relations of quantum mechanics. The obtained formulas are used to construct new operator representations of the colour Heisenberg Lie algebra. These representations are shown to be closely connected with some combinatorial identities and functional difference-differential interpolation formulae involving Euler numbers.
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