| 1. |
|
|
| 2. |
- Estrada, Karol, et al.
(författare)
-
Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.
- 2012
-
Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:5, s. 491-501
-
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.
|
|
| 3. |
- Hellström, Sara, et al.
(författare)
-
A follow up on the feasibility after national implementation of magnesium sulfate for neuroprotection prior to preterm birth.
- 2023
-
Ingår i: Acta obstetricia et gynecologica Scandinavica. - : John Wiley & Sons. - 1600-0412 .- 0001-6349. ; 102:12, s. 1741-1748
-
Tidskriftsartikel (refereegranskat)abstract
- The risk for brain injury manifested as cerebral palsy is higher in very preterm born children than in term. Prenatal administration of magnesium sulfate (MgSO4 ) has been shown to be neuroprotective and reduces the proportion of very preterm born children later diagnosed with cerebral palsy. A Swedish national clinical practice guideline was implemented in March 2020, stipulating the administration of a single intravenous dose of 6g MgSO4 1-24h prior to delivery before gestational age 32+0, aiming for 90% treatment coverage. The aim of this study was to evaluate the feasibility of this new clinical practice guideline in the first year of its implementation.Data on MgSO4 treatment were collected by reviewing the medical charts of women who gave birth to live born children in gestational age 22+0-31+6 during the period of March 1, 2020 to February 28, 2021, at five Swedish university hospitals. Women with pre-eclampsia, eclampsia, or high elevated liver enzymes low platelets (HELLP) were excluded.A total of 388 women were eligible and 79% received treatment with MgSO4 . Of the 21% not receiving treatment, 9% did not receive treatment due to lack of knowledge about the clinical practice guideline, 9% were not possible to treat and 3% had missing data. The proportion treated increased from 72% to 87% from the first to the last 3months. Of those treated, 81% received the drug within the stipulated timeframe (mean 8.7h, median 3.4h).There was a positive trend over time in the proportion of women receiving MgSO4 treatment, but the a priori target of 90% was not reached during the first year of implementation. Our findings indicate that this target could be reached with additional information to clinicians.
|
|
| 4. |
- Hemminki, Kari, et al.
(författare)
-
Germline genetics of cancer of unknown primary (CUP) and its specific subtypes
- 2016
-
Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:16, s. 22140-22149
-
Tidskriftsartikel (refereegranskat)abstract
- Cancer of unknown primary site (CUP) is a fatal cancer diagnosed through metastases at various organs. Little is known about germline genetics of CUP which appears worth of a search in view of reported familial associations in CUP. In the present study, samples from CUP patients were identified from 2 Swedish biobanks and a German clinical trial, totaling 578 CUP patients and 7628 regionally matched controls. Diagnostic data specified the organ where metastases were diagnosed. We carried out a genome-wide association study on CUP cases and controls. In the whole sample set, 6 loci reached an allelic p-value in the range of 10(-7) and were supported by data from the three centers. Three associations were located next to non-coding RNA genes. rs2660852 flanked 5' UTR of LTA4H (leukotriene A4 hydrolase), rs477145 was intronic to TIAM1 (T-cell lymphoma invasion and metastases) and rs2835931 was intronic to KCNJ6 (potassium channel, inwardly rectifying subfamily J, member 6). In analysis of subgroups of CUP patients (smokers, non-smokers and CUP with liver metastases) genome-wide significant associations were noted. For patients with liver metastases associations on chromosome 6 and 11, the latter including a cluster of genes DHCR7 and NADSYN1, encoding key enzymes in cholesterol and NAD synthesis, and KRTAP5-7, encoding a keratin associated protein. This first GWAS on CUP provide preliminary evidence that germline genes relating to inflammation (LTA4H), metastatic promotion (TIAM1) in association with lipid metabolic disturbance (chromosome 11 cluster) may contribute to the risk of CUP.
|
|
| 5. |
- Leo, P. J., et al.
(författare)
-
Defining the genetic susceptibility to cervical neoplasia-A genome-wide association study
- 2017
-
Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 13:8
-
Tidskriftsartikel (refereegranskat)abstract
- A small percentage of women with cervical HPV infection progress to cervical neoplasia, and the risk factors determining progression are incompletely understood. We sought to define the genetic loci involved in cervical neoplasia and to assess its heritability using unbiased unrelated case/control statistical approaches. We demonstrated strong association of cervical neoplasia with risk and protective HLA haplotypes that are determined by the amino-acids carried at positions 13 and 71 in pocket 4 of HLA-DRB1 and position 156 in HLA-B. Furthermore, 36% (standard error 2.4%) of liability of HPV-associated cervical pre-cancer and cancer is determined by common genetic variants. Women in the highest 10% of genetic risk scores have approximately > 7.1% risk, and those in the highest 5% have approximately > 21.6% risk, of developing cervical neoplasia. Future studies should examine genetic risk prediction in assessing the risk of cervical neoplasia further, in combination with other screening methods.
|
|
| 6. |
|
|
| 7. |
- Nethander, Maria, 1980, et al.
(författare)
-
An atlas of genetic determinants of forearm fracture.
- 2023
-
Ingår i: Nature genetics. - : Springer Nature. - 1546-1718 .- 1061-4036. ; 55:11, s. 1820-1830
-
Tidskriftsartikel (refereegranskat)abstract
- Osteoporotic fracture is among the most common and costly of diseases. While reasonably heritable, its genetic determinants have remained elusive. Forearm fractures are the most common clinically recognized osteoporotic fractures with a relatively high heritability. To establish an atlas of the genetic determinants of forearm fractures, we performed genome-wide association analyses including 100,026 forearm fracture cases. We identified 43 loci, including 26 new fracture loci. Although most fracture loci associated with bone mineral density, we also identified loci that primarily regulate bone quality parameters. Functional studies of one such locus, at TAC4, revealed that Tac4-/- mice have reduced mechanical bone strength. The strongest forearm fracture signal, at WNT16, displayed remarkable bone-site-specificity with no association with hip fractures. Tall stature and low body mass index were identified as new causal risk factors for fractures. The insights from this atlas may improve fracture prediction and enable therapeutic development to prevent fractures.
|
|
| 8. |
- Nethander, Maria, 1980, et al.
(författare)
-
BMD-Related Genetic Risk Scores Predict Site-Specific Fractures as Well as Trabecular and Cortical Bone Microstructure
- 2020
-
Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 105:4
-
Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: It is important to identify patients at highest risk of fractures. OBJECTIVE: To compare the separate and combined performances of bone-related genetic risk scores (GRSs) for prediction of forearm, hip and vertebral fractures separately, as well as of trabecular and cortical bone microstructure parameters separately. DESIGN, SETTING, AND PARTICIPANTS: Using 1103 single nucleotide polymorphisms (SNPs) independently associated with estimated bone mineral density of the heel (eBMD), we developed a weighted GRS for eBMD and determined its contribution to fracture prediction beyond 2 previously developed GRSs for femur neck BMD (49 SNPs) and lumbar spine BMD (48 SNPs). Associations between these GRSs and forearm (ncases = 1020; ncontrols = 2838), hip (ncases = 1123; ncontrols = 2630) and vertebral (ncases = 288; ncontrols = 1187) fractures were evaluated in 3 Swedish cohorts. Associations between the GRSs and trabecular and cortical bone microstructure parameters (n = 426) were evaluated in the MrOS Sweden cohort. RESULTS: We found that eBMDGRS was the only significant independent predictor of forearm and vertebral fractures while both FN-BMDGRS and eBMDGRS were significant independent predictors of hip fractures. The eBMDGRS was the major GRS contributing to prediction of trabecular bone microstructure parameters while both FN-BMDGRS and eBMDGRS contributed information for prediction of cortical bone microstructure parameters. CONCLUSIONS: The eBMDGRS independently predicts forearm and vertebral fractures while both FN-BMDGRS and eBMDGRS contribute independent information for prediction of hip fractures. We propose that eBMDGRS captures unique information about trabecular bone microstructure useful for prediction of forearm and vertebral fractures. These findings may facilitate personalized medicine to predict site-specific fractures as well as cortical and trabecular bone microstructure separately.
|
|
| 9. |
- Nilsson Sommar, Johan, et al.
(författare)
-
Hip Fracture Risk and Cadmium in Erythrocytes : A Nested Case-Control Study with Prospectively Collected Samples
- 2014
-
Ingår i: Calcified Tissue International. - : Springer. - 0171-967X .- 1432-0827. ; 94:2, s. 183-190
-
Tidskriftsartikel (refereegranskat)abstract
- Several studies have investigated the relation between bone mass density and cadmium exposure, but only few studies have been performed on fractures and biomarkers of cadmium. This study analyzed the association between hip fracture risk and cadmium in erythrocytes (Ery-Cd). Prospective samples from the Northern Sweden Health and Disease Study's biobank were used for 109 individuals who later in life had sustained a low-trauma hip fracture, matched with two controls of the same age and gender. The mean concentration of Ery-Cd (±SD) in case samples was 1.3 ± 1.4 versus 0.9 ± 1.0 μg/L in controls. The odds ratio (OR) was 1.63 [95 % confidence interval (CI) 1.10-2.42] for suffering a hip fracture for each microgram per liter increase in Ery-Cd. However, when taking smoking into consideration (never, former, or current), neither Ery-Cd nor smoking showed a statistically significant increase in fracture risk. Using multiple conditional logistic regression with BMI, height, and smoking, the estimated OR for a 1-μg/L increase in Ery-Cd was 1.52 (95 % CI 0.77-2.97). Subgroup analysis showed an increased fracture risk among women (OR = 1.94, 95 % CI 1.18-3.20, for a 1 μg/L increase), which also remained in the multiple analysis (OR = 3.33, 95 % CI 1.29-8.56). This study shows that fracture risk is associated with Ery-Cd. It is, however, not possible to draw firm conclusions on whether cadmium is the causal factor or whether other smoking-related factors cause this association. Subgroup analysis shows that cadmium is a risk factor for hip fracture among women.
|
|
| 10. |
|
|
