| 1. |
- Ackermann, M., et al.
(författare)
-
Periodic Emission from the Gamma-Ray Binary 1FGL J1018.6-5856
- 2012
-
Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 335:6065, s. 189-193
-
Tidskriftsartikel (refereegranskat)abstract
- Gamma-ray binaries are stellar systems containing a neutron star or black hole, with gamma-ray emission produced by an interaction between the components. These systems are rare, even though binary evolution models predict dozens in our Galaxy. A search for gamma-ray binaries with the Fermi Large Area Telescope (LAT) shows that 1FGL J1018.6-5856 exhibits intensity and spectral modulation with a 16.6-day period. We identified a variable x-ray counterpart, which shows a sharp maximum coinciding with maximum gamma-ray emission, as well as an O6V((f)) star optical counterpart and a radio counterpart that is also apparently modulated on the orbital period. 1FGL J1018.6-5856 is thus a gamma-ray binary, and its detection suggests the presence of other fainter binaries in the Galaxy.
|
|
| 2. |
- Palmer, Nicholette D, et al.
(författare)
-
A genome-wide association search for type 2 diabetes genes in African Americans.
- 2012
-
Ingår i: PloS one. - San Francisco : Public Library of Science (PLoS). - 1932-6203. ; 7:1, s. e29202-
-
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.
|
|
| 3. |
|
|
| 4. |
- Saxena, Richa, et al.
(författare)
-
Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge
- 2010
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:2, s. 142-148
-
Tidskriftsartikel (refereegranskat)abstract
- Glucose levels 2 h after an oral glucose challenge are a clinical measure of glucose tolerance used in the diagnosis of type 2 diabetes. We report a meta-analysis of nine genome-wide association studies (n = 15,234 nondiabetic individuals) and a follow-up of 29 independent loci (n = 6,958–30,620). We identify variants at the GIPR locus associated with 2-h glucose level (rs10423928, β (s.e.m.) = 0.09 (0.01) mmol/l per A allele, P = 2.0 × 10−15). The GIPR A-allele carriers also showed decreased insulin secretion (n = 22,492; insulinogenic index, P = 1.0 × 10−17; ratio of insulin to glucose area under the curve, P = 1.3 × 10−16) and diminished incretin effect (n = 804; P = 4.3 × 10−4). We also identified variants at ADCY5 (rs2877716, P = 4.2 × 10−16), VPS13C (rs17271305, P = 4.1 × 10−8), GCKR (rs1260326, P = 7.1 × 10−11) and TCF7L2 (rs7903146, P = 4.2 × 10−10) associated with 2-h glucose. Of the three newly implicated loci (GIPR, ADCY5 and VPS13C), only ADCY5 was found to be associated with type 2 diabetes in collaborating studies (n = 35,869 cases, 89,798 controls, OR = 1.12, 95% CI 1.09–1.15, P = 4.8 × 10−18).
|
|
| 5. |
- Voight, Benjamin F., et al.
(författare)
-
Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis
- 2010
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:7, s. 579-589
-
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.
|
|
| 6. |
- Scott, Robert A, et al.
(författare)
-
No interactions between previously associated 2-hour glucose gene variants and physical activity or BMI on 2-hour glucose levels
- 2012
-
Ingår i: Diabetes. - Alexandria, VA : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 61:5, s. 1291-1296
-
Tidskriftsartikel (refereegranskat)abstract
- Gene-lifestyle interactions have been suggested to contribute to the development of type 2 diabetes. Glucose levels 2 h after a standard 75-g glucose challenge are used to diagnose diabetes and are associated with both genetic and lifestyle factors. However, whether these factors interact to determine 2-h glucose levels is unknown. We meta-analyzed single nucleotide polymorphism (SNP) × BMI and SNP × physical activity (PA) interaction regression models for five SNPs previously associated with 2-h glucose levels from up to 22 studies comprising 54,884 individuals without diabetes. PA levels were dichotomized, with individuals below the first quintile classified as inactive (20%) and the remainder as active (80%). BMI was considered a continuous trait. Inactive individuals had higher 2-h glucose levels than active individuals (β = 0.22 mmol/L [95% CI 0.13-0.31], P = 1.63 × 10(-6)). All SNPs were associated with 2-h glucose (β = 0.06-0.12 mmol/allele, P ≤ 1.53 × 10(-7)), but no significant interactions were found with PA (P > 0.18) or BMI (P ≥ 0.04). In this large study of gene-lifestyle interaction, we observed no interactions between genetic and lifestyle factors, both of which were associated with 2-h glucose. It is perhaps unlikely that top loci from genome-wide association studies will exhibit strong subgroup-specific effects, and may not, therefore, make the best candidates for the study of interactions.
|
|
| 7. |
- Dimas, Antigone S, et al.
(författare)
-
Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity.
- 2014
-
Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 63:6, s. 2158-2171
-
Tidskriftsartikel (refereegranskat)abstract
- Patients with established type 2 diabetes display both beta-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci and indices of proinsulin processing, insulin secretion and insulin sensitivity. We included data from up to 58,614 non-diabetic subjects with basal measures, and 17,327 with dynamic measures. We employed additive genetic models with adjustment for sex, age and BMI, followed by fixed-effects inverse variance meta-analyses. Cluster analyses grouped risk loci into five major categories based on their relationship to these continuous glycemic phenotypes. The first cluster (PPARG, KLF14, IRS1, GCKR) was characterized by primary effects on insulin sensitivity. The second (MTNR1B, GCK) featured risk alleles associated with reduced insulin secretion and fasting hyperglycemia. ARAP1 constituted a third cluster characterized by defects in insulin processing. A fourth cluster (including TCF7L2, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without detectable change in fasting glucose. The final group contained twenty risk loci with no clear-cut associations to continuous glycemic traits. By assembling extensive data on continuous glycemic traits, we have exposed the diverse mechanisms whereby type 2 diabetes risk variants impact disease predisposition.
|
|
| 8. |
- Fontaine-Bisson, B., et al.
(författare)
-
Evaluating the discriminative power of multi-trait genetic risk scores for type 2 diabetes in a northern Swedish population
- 2010
-
Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 53:10, s. 2155-2162
-
Tidskriftsartikel (refereegranskat)abstract
- We determined whether single nucleotide polymorphisms (SNPs) previously associated with diabetogenic traits improve the discriminative power of a type 2 diabetes genetic risk score. Participants (n = 2,751) were genotyped for 73 SNPs previously associated with type 2 diabetes, fasting glucose/insulin concentrations, obesity or lipid levels, from which five genetic risk scores (one for each of the four traits and one combining all SNPs) were computed. Type 2 diabetes patients and non-diabetic controls (n = 1,327/1,424) were identified using medical records in addition to an independent oral glucose tolerance test. Model 1, including only SNPs associated with type 2 diabetes, had a discriminative power of 0.591 (p < 1.00 x 10(-20) vs null model) as estimated by the area under the receiver operator characteristic curve (ROC AUC). Model 2, including only fasting glucose/insulin SNPs, had a significantly higher discriminative power than the null model (ROC AUC 0.543; p = 9.38 x 10(-6) vs null model), but lower discriminative power than model 1 (p = 5.92 x 10(-5)). Model 3, with only lipid-associated SNPs, had significantly higher discriminative power than the null model (ROC AUC 0.565; p = 1.44 x 10(-9)) and was not statistically different from model 1 (p = 0.083). The ROC AUC of model 4, which included only obesity SNPs, was 0.557 (p = 2.30 x 10(-7) vs null model) and smaller than model 1 (p = 0.025). Finally, the model including all SNPs yielded a significant improvement in discriminative power compared with the null model (p < 1.0 x 10(-20)) and model 1 (p = 1.32 x 10(-5)); its ROC AUC was 0.626. Adding SNPs previously associated with fasting glucose, insulin, lipids or obesity to a genetic risk score for type 2 diabetes significantly increases the power to discriminate between people with and without clinically manifest type 2 diabetes compared with a model including only conventional type 2 diabetes loci.
|
|
| 9. |
- Huhtaniemi, Ilpo T, et al.
(författare)
-
Effect of Polymorphisms in Selected Genes Involved in Pituitary-Testicular Function on Reproductive Hormones and Phenotype in Aging Men.
- 2010
-
Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 95, s. 1898-1908
-
Tidskriftsartikel (refereegranskat)abstract
- Context: Polymorphisms in genes involved in regulation, biosynthesis, metabolism, and actions of testicular sex hormones may influence hormone balance and phenotype of aging men. Objective: We investigated the relationships between polymorphisms in genes related to pituitary-testicular endocrine function and health status. Design and Setting: Using cross-sectional baseline data, we conducted a multinational prospective cohort observational study consisting of a population survey of community-dwelling men. Participants: A total of 2748 men, aged 40-79 (mean +/- SD, 60.2 + 11.2) yr, were randomly recruited from eight European centers. Forty-three polymorphisms were genotyped in the following genes: androgen receptor (AR), estrogen receptor-alpha and -beta (ESR1 and ESR2), steroid 5alpha-reductase type II (SRD5A2), 17alpha-hydroxylase/17,20-lyase (CYP17A1), aromatase (CYP19A1), sex hormone-binding globulin (SHBG), LH beta-subunit (LHB), and LH receptor (LHCGR). Main Outcome Measures: We measured the associations between gene polymorphisms and endocrine, metabolic, and phenotypic parameters related to aging and sex hormone action. Results: Several polymorphisms in SHBG, ESR2, AR, CYP19A1, and LHB were significantly associated with circulating levels of SHBG, LH, total, free, and bioavailable testosterone and estradiol, the LH x testosterone product, and indices of insulin sensitivity. Apart from several previously reported associations between genes affecting estrogen levels and heel ultrasound parameters, no associations existed between polymorphisms and nonhormonal variables (anthropometry, blood lipids, blood pressure, hemoglobin, prostate symptoms, prostate-specific antigen, sexual dysfunction, cognition). Conclusion: In aging men, polymorphisms in genes related to the pituitary-testicular endocrine function significantly influence circulating LH, testosterone, and estradiol levels, but the downstream effects may be too small to influence secondary phenotypic parameters.
|
|
| 10. |
- Lee, David M., et al.
(författare)
-
Endogenous hormones, androgen receptor CAG repeat length and fluid cognition in middle-aged and older men: results from the European Male Ageing Study
- 2010
-
Ingår i: European Journal of Endocrinology. - 1479-683X. ; 162:6, s. 1155-1164
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: Data remain divergent regarding the activational effects of endogenous hormones on adult cognitive function. We examined the association between cognition, hormones and androgen receptor (AR) CAG repeat length in a large cohort of men. Design: Community-based, cross-sectional study of 3369 men aged 40-79 years. Methods: Cognition tests were the Rey-Osterrieth Complex Figure, Camden Topographical Recognition Memory and Digit-Symbol Substitution. A fluid cognition (FC) z-score was computed from the individual tests. Testosterone, oestradiol (OE2) and 5 alpha-dihydrotestosterone were measured by gas chromatography-mass spectrometry; DHEAS, LH, FSH and sex hormone-binding globulin (SHBG) by electrochemiluminescence. Free testosterone and OE2 were calculated from total hormone, SHBG and albumin. CAG repeat lengths were assayed by PCR genotyping. Results: Total testosterone and free testosterone were associated with higher FC z-scores, LH and FSH with lower FC z-scores in age-adjusted linear regressions. After adjusting for health, lifestyle and centre, a modest association was only observed between DHEAS and a lower FC z-score (beta=-0.011, P=0.02), although this was driven by subjects with DHEAS levels > 10 mu mol/l. Locally weighted plots revealed no threshold effects between hormones and FC. There was no association between CAG repeat length and FC z-score after adjustment for age and centre (beta=-0.007, P=0.06), nor any interaction effect between CAG repeat length and hormones. Conclusion: Our results suggest that endogenous hormones are not associated with a vision-based measure of FC among healthy, community-dwelling men. Further studies are warranted to determine whether 'high' DHEAS levels are associated with poorer performance on a broader range of neuropsychological tests.
|
|
