| 3581. |
- Lu, T. Y., et al.
(författare)
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Improved prediction of fracture risk leveraging a genome-wide polygenic risk score
- 2021
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Ingår i: Genome Medicine. - : Springer Science and Business Media LLC. - 1756-994X. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Accurately quantifying the risk of osteoporotic fracture is important for directing appropriate clinical interventions. While skeletal measures such as heel quantitative speed of sound (SOS) and dual-energy X-ray absorptiometry bone mineral density are able to predict the risk of osteoporotic fracture, the utility of such measurements is subject to the availability of equipment and human resources. Using data from 341,449 individuals of white British ancestry, we previously developed a genome-wide polygenic risk score (PRS), called gSOS, that captured 25.0% of the total variance in SOS. Here, we test whether gSOS can improve fracture risk prediction. Methods We examined the predictive power of gSOS in five genome-wide genotyped cohorts, including 90,172 individuals of European ancestry and 25,034 individuals of Asian ancestry. We calculated gSOS for each individual and tested for the association between gSOS and incident major osteoporotic fracture and hip fracture. We tested whether adding gSOS to the risk prediction models had added value over models using other commonly used clinical risk factors. Results A standard deviation decrease in gSOS was associated with an increased odds of incident major osteoporotic fracture in populations of European ancestry, with odds ratios ranging from 1.35 to 1.46 in four cohorts. It was also associated with a 1.26-fold (95% confidence interval (CI) 1.13-1.41) increased odds of incident major osteoporotic fracture in the Asian population. We demonstrated that gSOS was more predictive of incident major osteoporotic fracture (area under the receiver operating characteristic curve (AUROC) = 0.734; 95% CI 0.727-0.740) and incident hip fracture (AUROC = 0.798; 95% CI 0.791-0.805) than most traditional clinical risk factors, including prior fracture, use of corticosteroids, rheumatoid arthritis, and smoking. We also showed that adding gSOS to the Fracture Risk Assessment Tool (FRAX) could refine the risk prediction with a positive net reclassification index ranging from 0.024 to 0.072. Conclusions We generated and validated a PRS for SOS which was associated with the risk of fracture. This score was more strongly associated with the risk of fracture than many clinical risk factors and provided an improvement in risk prediction. gSOS should be explored as a tool to improve risk stratification to identify individuals at high risk of fracture.
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| 3582. |
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| 3583. |
- Lui, Julian C., et al.
(författare)
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EZH1 and EZH2 promote skeletal growth by repressing inhibitors of chondrocyte proliferation and hypertrophy
- 2016
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Ingår i: Nature Communications. - London, United Kingdom : Nature Publishing Group. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Histone methyltransferases EZH1 and EZH2 catalyse the trimethylation of histone H3 at lysine 27 (H3K27), which serves as an epigenetic signal for chromatin condensation and transcriptional repression. Genome-wide associated studies have implicated EZH2 in the control of height and mutations in EZH2 cause Weaver syndrome, which includes skeletal overgrowth. Here we show that the combined loss of Ezh1 and Ezh2 in chondrocytes severely impairs skeletal growth in mice. Both of the principal processes underlying growth plate chondrogenesis, chondrocyte proliferation and hypertrophy, are compromised. The decrease in chondrocyte proliferation is due in part to derepression of cyclin-dependent kinase inhibitors Ink4a/b, while ineffective chondrocyte hypertrophy is due to the suppression of IGF signalling by the increased expression of IGF-binding proteins. Collectively, our findings reveal a critical role for H3K27 methylation in the regulation of chondrocyte proliferation and hypertrophy in the growth plate, which are the central determinants of skeletal growth.
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| 3584. |
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| 3585. |
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| 3586. |
- Luo, R, et al.
(författare)
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Paternal DNA Methylation May Be Associated With Gestational Age at Birth
- 2020
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Ingår i: Epigenetics insights. - : SAGE Publications. - 2516-8657. ; 13, s. 2516865720930701-
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Tidskriftsartikel (refereegranskat)abstract
- How epigenetic modifications of DNA are associated with gestational age at birth is not fully understood. We investigated potential effects of differential paternal DNA methylation (DNAm) on offspring gestational age at birth by conducting an epigenome-wide search for cytosine-phosphate-guanine (CpG) sites. Methods: Study participants in this study consist of male cohort members or partners of the F1-generation of the Isle of Wight Birth Cohort (IoWBC). DNAm levels in peripheral blood from F1-fathers (n = 92) collected around pregnancy of their spouses were analyzed using the Illumina 450K array. A 5-step statistical analysis was performed. First, a training-testing screening approach was applied to select CpG sites that are potentially associated with gestational age at birth. Second, functional enrichment analysis was employed to identify biological processes. Third, by centralizing on biologically informative genes, Cox proportional hazards models were used to assess the hazard ratios of individual paternal CpGs on gestational age adjusting for confounders. Fourth, to assess the validity of our results, we compared our CpG-gestational age correlations within a Born into Life Study in Sweden (n = 15). Finally, we investigated the correlation between the detected CpGs and differential gene expression in F2 cord blood in the IoWBC. Results: Analysis of DNAm of fathers collected around their partner’s pregnancy identified 216 CpG sites significantly associated with gestational age at birth. Functional enrichment pathways analyses of the annotated genes revealed 2 biological pathways significantly related to cell-cell membrane adhesion molecules. Differential methylation of 9 cell membrane adhesion pathway-related CpGs were significantly associated with gestational age at birth after adjustment for confounders. The replication sample showed correlation coefficients of 2 pathway-related CpGs with gestational age at birth within 95% confidence intervals of correlation coefficients in IoWBC. Finally, CpG sites of protocadherin ( PCDH) gene clusters were associated with gene expression of PCDH in F2 cord blood. Conclusions: Our findings suggest that differential paternal DNAm may affect gestational age at birth through cell-cell membrane adhesion molecules. The results are novel but require future replication in a larger cohort.
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| 3587. |
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| 3588. |
- Luyapan, Jennifer, et al.
(författare)
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Candidate pathway analysis of surfactant proteins identifies CTSH and SFTA2 that influences lung cancer risk
- 2023
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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 32:18, s. 2842-2855
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Tidskriftsartikel (refereegranskat)abstract
- Pulmonary surfactant is a lipoprotein synthesized and secreted by alveolar type II cells in lung. We evaluated the associations between 200,139 single nucleotide polymorphisms (SNPs) of 40 surfactant-related genes and lung cancer risk using genotyped data from two independent lung cancer genome-wide association studies. Discovery data included 18,082 cases and 13,780 controls of European ancestry. Replication data included 1,914 cases and 3,065 controls of European descent. Using multivariate logistic regression, we found novel SNPs in surfactant-related genes CTSH [rs34577742 C > T, odds ratio (OR) = 0.90, 95% confidence interval (CI) = 0.89-0.93, P = 7.64 × 10-9] and SFTA2 (rs3095153 G > A, OR = 1.16, 95% CI = 1.10-1.21, P = 1.27 × 10-9) associated with overall lung cancer in the discovery data and validated in an independent replication data-CTSH (rs34577742 C > T, OR = 0.88, 95% CI = 0.80-0.96, P = 5.76 × 10-3) and SFTA2 (rs3095153 G > A, OR = 1.14, 95% CI = 1.01-1.28, P = 3.25 × 10-2). Among ever smokers, we found SNPs in CTSH (rs34577742 C > T, OR = 0.89, 95% CI = 0.85-0.92, P = 1.94 × 10-7) and SFTA2 (rs3095152 G > A, OR = 1.20, 95% CI = 1.14-1.27, P = 4.25 × 10-11) associated with overall lung cancer in the discovery data and validated in the replication data-CTSH (rs34577742 C > T, OR = 0.88, 95% CI = 0.79-0.97, P = 1.64 × 10-2) and SFTA2 (rs3095152 G > A, OR = 1.15, 95% CI = 1.01-1.30, P = 3.81 × 10-2). Subsequent transcriptome-wide association study using expression weights from a lung expression quantitative trait loci study revealed genes most strongly associated with lung cancer are CTSH (PTWAS = 2.44 × 10-4) and SFTA2 (PTWAS = 2.32 × 10-6).
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| 3589. |
- Löwemark, Ludvig, 1969-, et al.
(författare)
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New evidence for a glacioeustatic influence on deep watercirculation, bottom water ventilation and primaryproductivity in the South China Sea
- 2009
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Ingår i: Dynamics of atmospheres and oceans (Print). - : Elsevier. - 0377-0265 .- 1872-6879. ; 47:1-3, s. 138-153
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Tidskriftsartikel (refereegranskat)abstract
- We provide new evidence for the development of a stable estuarinecirculation characterized by stagnating water bodies, nutrientrecycling and increased primary productivity in the South ChinaSea (SCS) during glacial intervals. This circulation was caused bythe closure of the shallow and narrow straits connecting the SCSin the south and west. Our main evidence is derived from newlymeasured Mn concentrations and Mn/Al ratios in two sedimentcores from the northern and southeastern SCS covering the last500 ky. Concentrations and Mn/Al ratios of the redox sensitive elementMnshowclearglacial–interglacial cycles with maxima duringinterglacial periods and minima during glacial periods. These cyclesindicate ventilation cycles of the bottom water, and are connectedto the glacial–interglacial changes in sea level. In contrast, totalorganic carbon (TOC) concentrations display an opposite patternwith pronounced maxima during glacial times, especially in thesouthern part of the basin. The variations in TOC can be ascribed totwo factors. Firstly, variations in primary productivity are controlledby variations in the intensity of the winter monsoon. Secondlyto the degree of preservation of TOC controlled by variations inventilation, which in turn is ultimately controlled by sea level. Consequently, variations in TOC represent a superimposition ofprimarily sea level influenced preservation control and wintermonsoon driven variations in primary productivity intensity. Thedecrease in Mn correspond to times when sea level dropped40–60m below the present level. The larger amplitude of the variationsin TOC and Mn in the southern part of the basin compared tothe northern site suggest that oxygen depletion and nutrient recyclingwas stronger in the parts of the basin situated the furthest away from the only remaining opening to the open Pacific, the LuzonStrait.
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| 3590. |
- M. A. Hossain, B. Bohnenbuck, Y. D. Chuang, M. W. Haverkort, I. S. Elfimov, A.Tanaka, A. G. Cruz Gonzalez, Z. Hu, H.-J. Lin, C. T. Chen, R. Mathieu, Y. Tokura, Y. Yoshida, L. H. Tjeng, Z. Hussain, B. Keimer, G. A. Sawatzky and A. Damascelli
(författare)
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Mott versus Slater-type metal-insulator transition in Mn-substituted Sr3Ru2O7
- 2012
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Ingår i: Physical Review B Condensed Matter. - 0163-1829 .- 1095-3795. ; 86, s. 041102(R)-
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Tidskriftsartikel (refereegranskat)
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