| 1. |
- 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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| 2. |
- Su, Zhan, et al.
(författare)
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Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus.
- 2012
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:10
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Tidskriftsartikel (refereegranskat)abstract
- Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986 cases and 12,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p21, rs9257809 (Pcombined=4.09×10(-9); odds ratio (OR)=1.21, 95% confidence interval (CI)=1.13-1.28), within the major histocompatibility complex locus, and chromosome 16q24, rs9936833 (Pcombined=2.74×10(-10); OR=1.14, 95% CI=1.10-1.19), for which the closest protein-coding gene is FOXF1, which is implicated in esophageal development and structure. We found evidence that many common variants of small effect contribute to genetic susceptibility to Barrett's esophagus and that SNP alleles predisposing to obesity also increase risk for Barrett's esophagus.
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| 3. |
- Brooke, Hannah L, et al.
(författare)
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More of the same or a change of scenery : an observational study of variety and frequency of physical activity in British children.
- 2013
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Ingår i: BMC Public Health. - : Springer Science and Business Media LLC. - 1471-2458. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Physical activity is important for children's health, but successful physical activity promotion is challenging. Whether performing many different types of activities (Variety) is associated with higher physical activity independent of the number of activity sessions (Frequency) is unknown, but this information could inform physical activity promotion and public health strategies in children.METHODS: In the SPEEDY study we measured moderate-to-vigorous intensity physical activity (MVPA; ≥2000 counts/minute) over 7 days using GT1M Actigraph accelerometers in 1700 children from Norfolk, UK (56% girls, Mean ± SD 10.3 ± 0.3 years-old). Children reported participation in 28 leisure-time activities over the previous 7 days. Sex differences in activity participation were assessed using multilevel logistic regression, clustered by school. Associations of log-transformed MVPA with z-score-Variety (number of different activities/week) and z-score-Frequency (sum of all activity sessions/week) were examined using multilevel linear regression, adjusted for age, sex, parental education and age-standardised BMI.RESULTS: Children's activity participation often reflected gender stereotypes. Mean ± SD Variety was 10.8 ± 5.0 activities/week, and Frequency was 24.2±15.0 sessions/week. In separate models lnMVPA had similar strength, positive associations with z-score-Variety and z-score-Frequency (Exp β(95% CI); Variety 1.04(1.02-1.06), Frequency 1.04(1.02-1.06)). lnMVPA was not associated with z-score-Variety independent of z-score-Frequency (Variety 1.01(0.98-1.04), Frequency 1.03(1.00-1.06)).CONCLUSIONS: Future physical activity interventions and public health strategies could allow for gender specific activity preferences and could target both Variety and Frequency of activities participated in by children.
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| 4. |
- Brooke, Hannah L, et al.
(författare)
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Physical activity maintenance in the transition to adolescence : a longitudinal study of the roles of sport and lifestyle activities in British youth.
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:2
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Promoting physical activity in youth is important for health, but existing physical activity interventions have had limited success. We aimed to inform intervention design by i) describing drop-out, continuation and uptake of specific activities over the transition to adolescence; and ii) examining Variety (number of different activities/week) and Frequency (number of activity session/week) of activity participation and their associations with changes in objectively measured physical activity from childhood to adolescence.METHODS: At age 10.2±0.3 and 14.2±0.3 years, 319 children in the SPEEDY study (46% boys) wore GT1M Actigraph accelerometers for 7 days and provided self-reported participation (never, once, 2 to 3 times or four or more times, over the last 7 days) in 23 leisure-time activities. Associations of change in moderate-to-vigorous intensity PA (MVPA) (≥2000 counts/minute) and change in total physical activity (TPA) (average accelerometer counts/minute) with exposure variables Z-score transformed (change in) Variety and Frequency were examined using multilevel linear regression, clustered by school, in simple and adjusted models.RESULTS: The number of children ever reporting a specific activity ranged from 30 ('Hockey') to 279 ('Running or jogging'). Some activities were susceptible to drop-out (e.g. 'Skipping') but others were commonly continued or taken up (e.g. 'Household chores'). Overall, Variety and Frequency declined (mean±SD ΔVariety -3.1±4.4 activities/week; ΔFrequency -7.2±12.0 session/week). ΔMVPA and ΔTPA were not associated with Variety or Frequency at baseline, nor with ΔVariety or ΔFrequency (p>0.29 in all models).CONCLUSIONS: Popularity of specific activities as well as drop-out, continuation and uptake should be considered in future intervention development. Activities that are commonly continued or taken up may be more valuable to encourage in interventions than those with low participation or high drop-out. We did not find evidence to support the idea that Variety and Frequency may be key elements to include in future interventions.
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| 5. |
- Cheng, Xiaoxiao, et al.
(författare)
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Structure and Interactions of the Human Programmed Cell Death 1 Receptor
- 2013
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Ingår i: Journal of Biological Chemistry. - : American Society for Biochemistry and Molecular Biology. - 0021-9258 .- 1083-351X. ; 288:17, s. 11771-11785
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Tidskriftsartikel (refereegranskat)abstract
- PD-1, a receptor expressed by T cells, B cells, and monocytes, is a potent regulator of immune responses and a promising therapeutic target. The structure and interactions of human PD-1 are, however, incompletely characterized. We present the solution nuclear magnetic resonance (NMR)-based structure of the human PD-1 extracellular region and detailed analyses of its interactions with its ligands, PD-L1 and PD-L2. PD-1 has typical immunoglobulin superfamily topology but differs at the edge of the GFCC' sheet, which is flexible and completely lacks a C '' strand. Changes in PD-1 backbone NMR signals induced by ligand binding suggest that, whereas binding is centered on the GFCC' sheet, PD-1 is engaged by its two ligands differently and in ways incompletely explained by crystal structures of mouse PD-1.ligand complexes. The affinities of these interactions and that of PD-L1 with the costimulatory protein B7-1, measured using surface plasmon resonance, are significantly weaker than expected. The 3-4-fold greater affinity of PD-L2 versus PD-L1 for human PD-1 is principally due to the 3-fold smaller dissociation rate for PD-L2 binding. Isothermal titration calorimetry revealed that the PD-1/PD-L1 interaction is entropically driven, whereas PD-1/PD-L2 binding has a large enthalpic component. Mathematical simulations based on the biophysical data and quantitative expression data suggest an unexpectedly limited contribution of PD-L2 to PD-1 ligation during interactions of activated T cells with antigen-presenting cells. These findings provide a rigorous structural and biophysical framework for interpreting the important functions of PD-1 and reveal that potent inhibitory signaling can be initiated by weakly interacting receptors.
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| 6. |
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| 7. |
- Long, Gráinne H., et al.
(författare)
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Temporal shifts in cardiovascular risk factor distribution
- 2014
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Ingår i: American Journal of Preventive Medicine. - : Elsevier. - 0749-3797 .- 1873-2607. ; 46:2, s. 112-121
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Complementary strategies to shift risk factor population distributions and target high-risk individuals are required to reduce the burden of type 2 diabetes and cardiovascular disease (CVD).PURPOSE: To examine secular changes in glucose and CVD risk factors over 20 years during an individual and population-based CVD prevention program in Västerbotten County, Sweden.METHODS: Population-based health promotion intervention was conducted and annual invitation for individuals turning 40, 50, and 60 years to attend a health assessment, including an oral glucose tolerance test, biochemical measures, and a questionnaire. Data were collected between 1991 and 2010, analyzed in 2012 and available for 120,929 individuals. Linear regression modeling examined age-adjusted differences in CVD risk factor means over time. Data were direct-age-standardized to compare disease prevalence.RESULTS: Between 1991-1995 and 2006-2010, mean age-adjusted cholesterol (men=-0.53, 95% CI=-0.55, -0.50 mmol/L; women=-0.48, 95% CI=-0.50, -0.45 mmol/L) and systolic blood pressure declined (men=-3.06, 95% CI=-3.43, -2.70 mm Hg; women=-5.27, 95% CI=-5.64, -4.90 mm Hg), with corresponding decreases in the age-standardized prevalence of hypertension and hyperlipidemia. Mean age-adjusted 2-hour plasma glucose (men=0.19, 95% CI=0.15, 0.23 mmol/L; women=0.08, 95% CI=0.04, 0.11 mmol/L) and BMI increased (men=1.12, 95% CI=1.04, 1.21; women=0.65, 95% CI=0.55, 0.75), with increases in the age-standardized prevalence of diabetes and obesity.CONCLUSIONS: These data demonstrate the potential of combined individual- and population-based approaches to CVD risk factor control and highlight the need for additional strategies addressing hyperglycemia and obesity.
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| 8. |
- Voight, Benjamin F., et al.
(författare)
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Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:7, s. 579-589
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Tidskriftsartikel (refereegranskat)abstract
- By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P < 5 x 10(-8). These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.
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| 9. |
- Warren, Wesley C, et al.
(författare)
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The genome of a songbird
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7289, s. 757-762
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Tidskriftsartikel (refereegranskat)abstract
- The zebra finch is an important model organism in several fields with unique relevance to human neuroscience. Like other songbirds, the zebra finch communicates through learned vocalizations, an ability otherwise documented only in humans and a few other animals and lacking in the chicken-the only bird with a sequenced genome until now. Here we present a structural, functional and comparative analysis of the genome sequence of the zebra finch (Taeniopygia guttata), which is a songbird belonging to the large avian order Passeriformes. We find that the overall structures of the genomes are similar in zebra finch and chicken, but they differ in many intrachromosomal rearrangements, lineage-specific gene family expansions, the number of long-terminal-repeat-based retrotransposons, and mechanisms of sex chromosome dosage compensation. We show that song behaviour engages gene regulatory networks in the zebra finch brain, altering the expression of long non-coding RNAs, microRNAs, transcription factors and their targets. We also show evidence for rapid molecular evolution in the songbird lineage of genes that are regulated during song experience. These results indicate an active involvement of the genome in neural processes underlying vocal communication and identify potential genetic substrates for the evolution and regulation of this behaviour.
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