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- Newton-Cheh, Christopher, et al.
(författare)
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Genome-wide association study identifies eight loci associated with blood pressure
- 2009
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:6, s. 666-676
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Tidskriftsartikel (refereegranskat)abstract
- Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N <= 71,225 European ancestry, N <= 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 x 10(-24)), CYP1A2 (P = 1 x 10(-23)), FGF5 (P = 1 x 10(-21)), SH2B3 (P = 3 x 10(-18)), MTHFR (P = 2 x 10(-13)), c10orf107 (P = 1 x 10(-9)), ZNF652 (P = 5 x 10(-9)) and PLCD3 (P = 1 x 10(-8)) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.
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| 3. |
- Cox, Angela, et al.
(författare)
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A common coding variant in CASP8 is associated with breast cancer risk
- 2007
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 39:3, s. 352-358
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Tidskriftsartikel (refereegranskat)abstract
- The Breast Cancer Association Consortium (BCAC) has been established to conduct combined case-control analyses with augmented statistical power to try to confirm putative genetic associations with breast cancer. We genotyped nine SNPs for which there was some prior evidence of an association with breast cancer: CASP8 D302H (rs1045485), IGFBP3 -202 C --> A (rs2854744), SOD2 V16A (rs1799725), TGFB1 L10P (rs1982073), ATM S49C (rs1800054), ADH1B 3' UTR A --> G (rs1042026), CDKN1A S31R (rs1801270), ICAM5 V301I (rs1056538) and NUMA1 A794G (rs3750913). We included data from 9-15 studies, comprising 11,391-18,290 cases and 14,753-22,670 controls. We found evidence of an association with breast cancer for CASP8 D302H (with odds ratios (OR) of 0.89 (95% confidence interval (c.i.): 0.85-0.94) and 0.74 (95% c.i.: 0.62-0.87) for heterozygotes and rare homozygotes, respectively, compared with common homozygotes; P(trend) = 1.1 x 10(-7)) and weaker evidence for TGFB1 L10P (OR = 1.07 (95% c.i.: 1.02-1.13) and 1.16 (95% c.i.: 1.08-1.25), respectively; P(trend) = 2.8 x 10(-5)). These results demonstrate that common breast cancer susceptibility alleles with small effects on risk can be identified, given sufficiently powerful studies.
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| 5. |
- Chan, T., et al.
(författare)
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DECOVALEX III BMT3/BENCHPAR WP4 : The thermo-hydro-mechanical responses to a glacial cycle and their potential implications for deep geological disposal of nuclear fuel waste in a fractured crystalline rock mass
- 2005
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Ingår i: International Journal of Rock Mechanics And Mining Sciences. - : Elsevier BV. - 1365-1609 .- 1873-4545. ; 42:5-6, s. 805-827
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Tidskriftsartikel (refereegranskat)abstract
- A number of studies related to past and on-going deep repository performance assessments have identified glaciation/ deglaciation as major future events in the next few hundred thousand years capable of causing significant impact on the long term performance of the repository system. Benchmark Test 3 (BMT3) of the international DECOVALEX III project has been designed to provide an illustrative example that explores the mechanical and hydraulic response of a fractured crystalline rock mass to a period of glaciation. The primary purpose of this numerical study is to investigate whether transient events associated with a glacial cycle could significantly influence the performance of a deep geological repository in a crystalline Shield setting. A conceptual site-scale (tens of kilometres) hydro-mechanical (HM) model was assembled based primarily on site-specific litho-structural, hydrogeological and geomechanical data from the Whiteshell Research Area in the Canadian Shield, with simplification and generalization. Continental glaciological modelling of the Laurentide ice sheet through the last glacial cycle lasting approximately 100,000 years suggests that this site was glaciated at about 60 ka and between about 22.5 and 11 ka before present with maximum ice sheet thickness reaching 2500 m and maximum basal water pressure head reaching 2000m. The ice-sheet/drainage model was scaled down to generate spatially and temporally variable hydraulic and mechanical glaciated surface boundary conditions for site-scale subsurface HM modelling and permafrost modelling. Under extreme periglacial conditions permafrost was able to develop down to the assumed 500-m repository horizon. Two- and three-dimensional coupled HM finite-element simulations indicate: during ice-sheet advance there is rapid rise in hydraulic head, high transient hydraulic gradients and high groundwater velocities 2-3 orders of magnitude higher than under nonglacial conditions; surface water recharges deeper than under nonglacial conditions; upon ice-sheet retreat, the gradients reverse; fracture zone network geometry, interconnectivity and hydraulic properties significantly influence flow domain response; residual elevated heads are preserved for 10,000s in the low-diffusivity rock; and no hydraulic jacking or shear failure occurs at depth. It was found that transient coupled modelling is necessary to capture the essence of glacial effects on Performance Assessment. Model dimensionality also significantly affects simulated results.
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