| 11. |
- Kilpeläinen, Tuomas O, et al.
(författare)
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Physical activity attenuates the influence of FTO variants on obesity risk: a meta-analysis of 218,166 adults and 19,268 children.
- 2011
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Ingår i: PLoS medicine. - : Public Library of Science (PLoS). - 1549-1676 .- 1549-1277. ; 8:11
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n=218,166) and nine studies of children and adolescents (n=19,268). METHODS AND FINDINGS: All studies identified to have data on the FTO rs9939609 variant (or any proxy [r(2)>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25% of adults and 13% of children were categorized as inactive. Interaction analyses were performed within each study by including the FTO×PA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A-) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95% CI 1.20-1.26), but PA attenuated this effect (p(interaction) =0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio =1.22/allele, 95% CI 1.19-1.25) than in the inactive group (odds ratio =1.30/allele, 95% CI 1.24-1.36). No such interaction was found in children and adolescents. CONCLUSIONS: The association of the FTO risk allele with the odds of obesity is attenuated by 27% in physically active adults, highlighting the importance of PA in particular in those genetically predisposed to obesity.
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| 12. |
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| 13. |
- Stacey, Simon N, et al.
(författare)
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A germline variant in the TP53 polyadenylation signal confers cancer susceptibility.
- 2011
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 43:11, s. 1098-103
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Tidskriftsartikel (refereegranskat)abstract
- To identify new risk variants for cutaneous basal cell carcinoma, we performed a genome-wide association study of 16 million SNPs identified through whole-genome sequencing of 457 Icelanders. We imputed genotypes for 41,675 Illumina SNP chip-typed Icelanders and their relatives. In the discovery phase, the strongest signal came from rs78378222[C] (odds ratio (OR) = 2.36, P = 5.2 × 10(-17)), which has a frequency of 0.0192 in the Icelandic population. We then confirmed this association in non-Icelandic samples (OR = 1.75, P = 0.0060; overall OR = 2.16, P = 2.2 × 10(-20)). rs78378222 is in the 3' untranslated region of TP53 and changes the AATAAA polyadenylation signal to AATACA, resulting in impaired 3'-end processing of TP53 mRNA. Investigation of other tumor types identified associations of this SNP with prostate cancer (OR = 1.44, P = 2.4 × 10(-6)), glioma (OR = 2.35, P = 1.0 × 10(-5)) and colorectal adenoma (OR = 1.39, P = 1.6 × 10(-4)). However, we observed no effect for breast cancer, a common Li-Fraumeni syndrome tumor (OR = 1.06, P = 0.57, 95% confidence interval 0.88-1.27).
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| 14. |
- Carroll, R. K., et al.
(författare)
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Identification of an intracellular M17 family leucine aminopeptidase that is required for virulence in Staphylococcus aureus
- 2012
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Ingår i: Microbes and Infection. - : Elsevier BV. - 1286-4579. ; 14:11, s. 989-999
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Tidskriftsartikel (refereegranskat)abstract
- Staphylococcus aureus is a highly virulent bacterial pathogen capable of causing a variety of ailments throughout the human body. It is a major public health concern due to the continued emergence of highly pathogenic methicillin resistant strains (MRSA) both within hospitals and in the community. Virulence in S. aureus is mediated by an array of secreted and cell wall associated virulence factors, including toxins, hemolysins and proteases. In this work we identify a (l) under bar eucine (a) under bar mino (p) under bar eptidase (LAP, pepZ) that strongly impacts the pathogenic abilities of S. aureus. Disruption of the pepZ gene in either Newman or USA300 resulted in a dramatic attenuation of virulence in both localized and systemic models of infection. LAP is required for survival inside human macrophages and gene expression analysis shows that pepZ expression is highest in the intracellular environment. We examine the cellular location of LAP and demonstrate that it is localized to the bacterial cytosol. These results identify for the first time an intracellular leucine aminopeptidase that influences disease causation in a Gram-positive bacterium. (C) 2012 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.
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| 15. |
- Fall, Tove, et al.
(författare)
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The Role of Adiposity in Cardiometabolic Traits : A Mendelian Randomization Analysis
- 2013
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Ingår i: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 10:6, s. e1001474-
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Tidskriftsartikel (refereegranskat)abstract
- Background: The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach. Methods and Findings: We used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV) for body mass index (BMI) in a Mendelian randomization design. Thirty-six population-based studies of individuals of European descent contributed to the analyses. Age-and sex-adjusted regression models were fitted to test for association between (i) rs9939609 and BMI (n = 198,502), (ii) rs9939609 and 24 traits, and (iii) BMI and 24 traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators were compared to the BMI-trait associations derived from the same individuals. In the IV analysis, we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio, 1.19 per BMI-unit increase; 95% CI, 1.03-1.39) and replicated earlier reports of a causal association with type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension (odds ratio for IV estimator, 1.1-1.4; all p<0.05). For quantitative traits, our results provide novel evidence for a causal effect of adiposity on the liver enzymes alanine aminotransferase and gamma-glutamyl transferase and confirm previous reports of a causal effect of adiposity on systolic and diastolic blood pressure, fasting insulin, 2-h post-load glucose from the oral glucose tolerance test, C-reactive protein, triglycerides, and high-density lipoprotein cholesterol levels (all p<0.05). The estimated causal effects were in agreement with traditional observational measures in all instances except for type 2 diabetes, where the causal estimate was larger than the observational estimate (p = 0.001). Conclusions: We provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.
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| 16. |
- Fynbo, J. P. U., et al.
(författare)
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On the two high-metallicity DLAs at z=2.412 and 2.583 towards Q 0918+1636
- 2013
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 436:1, s. 361-370
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Tidskriftsartikel (refereegranskat)abstract
- The quasar Q0918+1636 (z = 3.07) has two intervening high-metallicity Damped Lyman a Absorbers (DLAs) along the line of sight, at redshifts of z = 2.412 and 2.583. The z = 2.583 DLA is located at a large impact parameter of 16.2 kpc, and despite this large impact parameter it has a very high metallicity (consistent with solar), a substantial fraction of H-2 molecules and it is dusty as inferred from the reddened spectrum of the background QSO. The z = 2.412 DLA has a metallicity of [M/H] = -0.6 (based on Zn II and Si II). In this paper we present new observations of this interesting sightline consisting of deep multiband imaging and further VLT spectroscopy. By fitting stellar population synthesis models to the photometric Spectral Energy Distribution we constrain the physical properties of the z = 2.583 DLA galaxy, and we infer its morphology by fitting a Sersic model to its surface brightness profile. We find it to be a relatively massive (M-* approximate to 10(10) M-circle dot), strongly star-forming (SFR approximate to 30 M-circle dot yr(-1)), dusty (E(B - V) = 0.4) galaxy with a disc-like morphology. We detect strong emission lines from the z = 2.583 DLA ([O II] lambda 3727, [O III] lambda lambda 4960, 5007, H beta and H alpha, albeit at low signal-to-noise ratio except for the [O III] lambda 5007 line). The metallicity derived from the emission lines is consistent with the absorption metallicity (12 + log (O/H) = 8.8 +/- 0.2). We also detect [O III] lambda 5007 emission from the galaxy counterpart of the z = 2.412 DLA at a small impact parameter (<2 kpc). Overall our findings are consistent with the emerging picture that high-metallicity DLAs are associated with relatively luminous and massive galaxy counterparts, compared to typical DLAs.
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