| 26. |
- Qi, Qibin, et al.
(författare)
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FTO genetic variants, dietary intake and body mass index : insights from 177 330 individuals
- 2014
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:25, s. 6961-6972
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Tidskriftsartikel (refereegranskat)abstract
- FTO is the strongest known genetic susceptibility locus for obesity. Experimental studies in animals suggest the potential roles of FTO in regulating food intake. The interactive relation among FTO variants, dietary intake and body mass index (BMI) is complex and results from previous often small-scale studies in humans are highly inconsistent. We performed large-scale analyses based on data from 177 330 adults (154 439 Whites, 5776 African Americans and 17 115 Asians) from 40 studies to examine: (i) the association between the FTO-rs9939609 variant (or a proxy single-nucleotide polymorphism) and total energy and macronutrient intake and (ii) the interaction between the FTO variant and dietary intake on BMI. The minor allele (A-allele) of the FTO-rs9939609 variant was associated with higher BMI in Whites (effect per allele = 0.34 [0.31, 0.37] kg/m(2), P = 1.9 × 10(-105)), and all participants (0.30 [0.30, 0.35] kg/m(2), P = 3.6 × 10(-107)). The BMI-increasing allele of the FTO variant showed a significant association with higher dietary protein intake (effect per allele = 0.08 [0.06, 0.10] %, P = 2.4 × 10(-16)), and relative weak associations with lower total energy intake (-6.4 [-10.1, -2.6] kcal/day, P = 0.001) and lower dietary carbohydrate intake (-0.07 [-0.11, -0.02] %, P = 0.004). The associations with protein (P = 7.5 × 10(-9)) and total energy (P = 0.002) were attenuated but remained significant after adjustment for BMI. We did not find significant interactions between the FTO variant and dietary intake of total energy, protein, carbohydrate or fat on BMI. Our findings suggest a positive association between the BMI-increasing allele of FTO variant and higher dietary protein intake and offer insight into potential link between FTO, dietary protein intake and adiposity.
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| 27. |
- Schmit, Stephanie L, et al.
(författare)
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Novel Common Genetic Susceptibility Loci for Colorectal Cancer.
- 2019
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 111:2, s. 146-157
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk.Methods: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided.Results: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0.Conclusions: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.
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| 28. |
- Takeuchi, Fumihiko, et al.
(författare)
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Interethnic analyses of blood pressure loci in populations of East Asian and European descent
- 2018
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Blood pressure (BP) is a major risk factor for cardiovascular disease and more than 200 genetic loci associated with BP are known. Here, we perform a multi-stage genome-wide association study for BP (max N = 289,038) principally in East Asians and meta-analysis in East Asians and Europeans. We report 19 new genetic loci and ancestry-specific BP variants, conforming to a common ancestry-specific variant association model. At 10 unique loci, distinct non-rare ancestry-specific variants colocalize within the same linkage disequilibrium block despite the significantly discordant effects for the proxy shared variants between the ethnic groups. The genome-wide transethnic correlation of causal-variant effect-sizes is 0.898 and 0.851 for systolic and diastolic BP, respectively. Some of the ancestry-specific association signals are also influenced by a selective sweep. Our results provide new evidence for the role of common ancestry-specific variants and natural selection in ethnic differences in complex traits such as BP.
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| 29. |
- Adam, R. M., et al.
(författare)
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The XXL Survey: LI. Pressure profile and Y SZ -M scaling relation in three low-mass galaxy clusters at z∼1 observed with NIKA2
- 2024
-
Ingår i: Astronomy and Astrophysics. - 0004-6361 .- 1432-0746. ; 684
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Tidskriftsartikel (refereegranskat)abstract
- Context. The thermodynamical properties of the intracluster medium (ICM) are driven by scale-free gravitational collapse, but they also reflect the rich astrophysical processes at play in galaxy clusters. At low masses (∼1014M) and high redshift (z≳1), these properties remain poorly constrained, observationally speaking, due to the difficulty in obtaining resolved and sensitive data. Aims. We aim to investigate the inner structure of the ICM as seen through the Sunyaev-Zel’dovich (SZ) effect in this regime of mass and redshift. We focused on the thermal pressure profile and the scaling relation between SZ flux and mass, namely the YSZ-M scaling relation. Methods. The three galaxy clusters XLSSC 072 (z=1.002), XLSSC 100 (z=0.915), and XLSSC 102 (z=0.969), with M500∼2×1014M, were selected from the XXL X-ray survey and observed with the NIKA2 millimeter camera to image their SZ signal. XMM-Newton X-ray data were used as a complement to the NIKA2 data to derive masses based on the YX-M relation and the hydrostatic equilibrium. Results. The SZ images of the three clusters, along with the X-ray and optical data, indicate dynamical activity related to merging events. The pressure profile is consistent with that expected for morphologically disturbed systems, with a relatively flat core and a shallow outer slope. Despite significant disturbances in the ICM, the three high-redshift low-mass clusters follow the YSZ-M relation expected from standard evolution remarkably well. Conclusions. These results indicate that the dominant physics that drives cluster evolution is already in place by z∼1, at least for systems with masses above M500∼1014M.
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| 30. |
- Chen, Bing, et al.
(författare)
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Source Forensics of Black Carbon Aerosols from China
- 2013
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Ingår i: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 47:16, s. 9102-9108
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Tidskriftsartikel (refereegranskat)abstract
- The limited understanding of black carbon (BC) aerosol emissions from incomplete combustion causes a poorly constrained anthropogenic climate warming that globally may be second only to CO2 and regionally, such as over East Asia, the dominant driver of climate change. The relative contribution to atmospheric BC from fossil fuel versus biomass combustion is important to constrain as fossil BC is a stronger climate forcer. The source apportionment is the underpinning for targeted mitigation actions. However, technology-based bottom-up emission inventories are inconclusive, largely due to uncertain BC emission factors from small-scale/household combustion and open burning. We use top-down radiocarbon measurements of atmospheric BC from five sites including three city sites and two regional sites to determine that fossil fuel combustion produces 80 +/- 6% of the BC emitted from China. This source-diagnostic radiocarbon signal in the ambient aerosol over East Asia establishes a much larger role for fossil fuel combustion than suggested by all 15 BC emission inventory models, including one with monthly resolution. Our results suggest that current climate modeling should refine both BC emission strength and consider the stronger radiative absorption associated with fossil-fuel-derived BC. To mitigate near-term climate effects and improve air quality in East Asia, activities such as residential coal combustion and city traffic should be targeted.
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| 31. |
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| 32. |
- Feigin, Valery L., et al.
(författare)
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Global, regional, and national burden of stroke and its risk factors, 1990-2019 : a systematic analysis for the Global Burden of Disease Study 2019
- 2021
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Ingår i: Lancet Neurology. - : Elsevier. - 1474-4422 .- 1474-4465. ; 20:10, s. 795-820
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Tidskriftsartikel (refereegranskat)abstract
- Background Regularly updated data on stroke and its pathological types, including data on their incidence, prevalence, mortality, disability, risk factors, and epidemiological trends, are important for evidence-based stroke care planning and resource allocation. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) aims to provide a standardised and comprehensive measurement of these metrics at global, regional, and national levels. Methods We applied GBD 2019 analytical tools to calculate stroke incidence, prevalence, mortality, disability-adjusted life-years (DALYs), and the population attributable fraction (PAF) of DALYs (with corresponding 95% uncertainty intervals [UIs]) associated with 19 risk factors, for 204 countries and territories from 1990 to 2019. These estimates were provided for ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage, and all strokes combined, and stratified by sex, age group, and World Bank country income level. Findings In 2019, there were 12.2 million (95% UI 11.0-13.6) incident cases of stroke, 101 million (93.2-111) prevalent cases of stroke, 143 million (133-153) DALYs due to stroke, and 6.55 million (6.00-7.02) deaths from stroke. Globally, stroke remained the second-leading cause of death (11.6% [10.8-12.2] of total deaths) and the third-leading cause of death and disability combined (5.7% [5.1-6.2] of total DALYs) in 2019. From 1990 to 2019, the absolute number of incident strokes increased by 70.0% (67.0-73.0), prevalent strokes increased by 85.0% (83.0-88.0), deaths from stroke increased by 43.0% (31.0-55.0), and DALYs due to stroke increased by 32.0% (22.0-42.0). During the same period, age-standardised rates of stroke incidence decreased by 17.0% (15.0-18.0), mortality decreased by 36.0% (31.0-42.0), prevalence decreased by 6.0% (5.0-7.0), and DALYs decreased by 36.0% (31.0-42.0). However, among people younger than 70 years, prevalence rates increased by 22.0% (21.0-24.0) and incidence rates increased by 15.0% (12.0-18.0). In 2019, the age-standardised stroke-related mortality rate was 3.6 (3.5-3.8) times higher in the World Bank low-income group than in the World Bank high-income group, and the age-standardised stroke-related DALY rate was 3.7 (3.5-3.9) times higher in the low-income group than the high-income group. Ischaemic stroke constituted 62.4% of all incident strokes in 2019 (7.63 million [6.57-8.96]), while intracerebral haemorrhage constituted 27.9% (3.41 million [2.97-3.91]) and subarachnoid haemorrhage constituted 9.7% (1.18 million [1.01-1.39]). In 2019, the five leading risk factors for stroke were high systolic blood pressure (contributing to 79.6 million [67.7-90.8] DALYs or 55.5% [48.2-62.0] of total stroke DALYs), high body-mass index (34.9 million [22.3-48.6] DALYs or 24.3% [15.7-33.2]), high fasting plasma glucose (28.9 million [19.8-41.5] DALYs or 20.2% [13.8-29.1]), ambient particulate matter pollution (28.7 million [23.4-33.4] DALYs or 20.1% [16.6-23.0]), and smoking (25.3 million [22.6-28.2] DALYs or 17.6% [16.4-19.0]). Interpretation The annual number of strokes and deaths due to stroke increased substantially from 1990 to 2019, despite substantial reductions in age-standardised rates, particularly among people older than 70 years. The highest age-standardised stroke-related mortality and DALY rates were in the World Bank low-income group. The fastest-growing risk factor for stroke between 1990 and 2019 was high body-mass index. Without urgent implementation of effective primary prevention strategies, the stroke burden will probably continue to grow across the world, particularly in low-income countries.
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| 33. |
- Hibou, F, et al.
(författare)
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Comparison of eta and eta ' production in the pp -> pp eta(eta ') reactions near threshold
- 1998
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Ingår i: PHYSICS LETTERS B. - : ELSEVIER SCIENCE BV. - 0370-2693. ; 438:1-2, s. 41-46
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Tidskriftsartikel (refereegranskat)abstract
- The total cross section of the pp --> pp eta' reaction has been measured at two energies near threshold by detecting the final protons in a magnetic spectrometer. The values obtained are about a factor of 70 less than for the corresponding eta production,
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| 34. |
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| 35. |
- Huang, Joyce Y., et al.
(författare)
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Circulating markers of cellular immune activation in prediagnostic blood sample and lung cancer risk in the Lung Cancer Cohort Consortium (LC3)
- 2020
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Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 146:9, s. 2394-2405
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Tidskriftsartikel (refereegranskat)abstract
- Cell-mediated immune suppression may play an important role in lung carcinogenesis. We investigated the associations for circulating levels of tryptophan, kynurenine, kynurenine:tryptophan ratio (KTR), quinolinic acid (QA) and neopterin as markers of immune regulation and inflammation with lung cancer risk in 5,364 smoking-matched case-control pairs from 20 prospective cohorts included in the international Lung Cancer Cohort Consortium. All biomarkers were quantified by mass spectrometry-based methods in serum/plasma samples collected on average 6 years before lung cancer diagnosis. Odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer associated with individual biomarkers were calculated using conditional logistic regression with adjustment for circulating cotinine. Compared to the lowest quintile, the highest quintiles of kynurenine, KTR, QA and neopterin were associated with a 20-30% higher risk, and tryptophan with a 15% lower risk of lung cancer (all p(trend) < 0.05). The strongest associations were seen for current smokers, where the adjusted ORs (95% CIs) of lung cancer for the highest quintile of KTR, QA and neopterin were 1.42 (1.15-1.75), 1.42 (1.14-1.76) and 1.45 (1.13-1.86), respectively. A stronger association was also seen for KTR and QA with risk of lung squamous cell carcinoma followed by adenocarcinoma, and for lung cancer diagnosed within the first 2 years after blood draw. This study demonstrated that components of the tryptophan-kynurenine pathway with immunomodulatory effects are associated with risk of lung cancer overall, especially for current smokers. Further research is needed to evaluate the role of these biomarkers in lung carcinogenesis and progression.
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| 36. |
- Kitahara, Cari M., et al.
(författare)
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Anthropometric Factors and Thyroid Cancer Risk by Histological Subtype : Pooled Analysis of 22 Prospective Studies
- 2016
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Ingår i: Thyroid. - : MARY ANN LIEBERT, INC. - 1050-7256 .- 1557-9077. ; 26:2, s. 306-318
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Tidskriftsartikel (refereegranskat)abstract
- Background: Greater height and body mass index (BMI) have been associated with an increased risk of thyroid cancer, particularly papillary carcinoma, the most common and least aggressive subtype. Few studies have evaluated these associations in relation to other, more aggressive histologic types or thyroid cancer-specific mortality. Methods: This large pooled analysis of 22 prospective studies (833,176 men and 1,260,871 women) investigated thyroid cancer incidence associated with greater height, BMI at baseline and young adulthood, and adulthood BMI gain (difference between young-adult and baseline BMI), overall and separately by sex and histological subtype using multivariable Cox proportional hazards regression models. Associations with thyroid cancer mortality were investigated in a subset of cohorts (578,922 men and 774,373 women) that contributed cause of death information. Results: During follow-up, 2996 incident thyroid cancers and 104 thyroid cancer deaths were identified. All anthropometric factors were positively associated with thyroid cancer incidence: hazard ratios (HR) [confidence intervals (CIs)] for height (per 5cm)=1.07 [1.04-1.10], BMI (per 5kg/m(2))=1.06 [1.02-1.10], waist circumference (per 5cm)=1.03 [1.01-1.05], young-adult BMI (per 5kg/m(2))=1.13 [1.02-1.25], and adulthood BMI gain (per 5kg/m(2))=1.07 [1.00-1.15]. Associations for baseline BMI and waist circumference were attenuated after mutual adjustment. Baseline BMI was more strongly associated with risk in men compared with women (p=0.04). Positive associations were observed for papillary, follicular, and anaplastic, but not medullary, thyroid carcinomas. Similar, but stronger, associations were observed for thyroid cancer mortality. Conclusion: The results suggest that greater height and excess adiposity throughout adulthood are associated with higher incidence of most major types of thyroid cancer, including the least common but most aggressive form, anaplastic carcinoma, and higher thyroid cancer mortality. Potential underlying biological mechanisms should be explored in future studies.
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| 37. |
- Kreckel, Holger, et al.
(författare)
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High-resolution storage-ring measurements of the dissociative recombination of H-3(+) using a supersonic expansion ion source
- 2010
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Ingår i: Physical Review A. Atomic, Molecular, and Optical Physics. - 1050-2947 .- 1094-1622. ; 82:4, s. 042715-
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Tidskriftsartikel (refereegranskat)abstract
- We have performed measurements of the dissociative electron recombination (DR) of H-3(+) at the ion storage ring TSR utilizing a supersonic expansion ion source. The ion source has been characterized by continuous wave cavity ring-down spectroscopy. We present high-resolution DR rate coefficients for different nuclear spin modifications of H-3(+) combined with precise fragment imaging studies of the internal excitation of the H-3(+) ions inside the storage ring. The measurements resolve changes in the energy dependence between the ortho-H-3(+) and para-H-3(+) rate coefficients at low center-of-mass collision energies. Analysis of the imaging data indicates that the stored H-3(+) ions may have higher rotational temperatures than previously assumed, most likely due to collisional heating during the extraction of the ions from the ion source. Simulations of the ion extraction shed light on possible origins of the heating process and how to avoid it in future experiments.
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| 38. |
- Laitman, Yael, et al.
(författare)
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Haplotype analysis of the 185delAG BRCA1 mutation in ethnically diverse populations
- 2013
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Ingår i: European Journal of Human Genetics. - London : Nature Publishing Group. - 1018-4813 .- 1476-5438. ; 21:2, s. 212-216
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Tidskriftsartikel (refereegranskat)abstract
- The 185delAG* BRCA1 mutation is encountered primarily in Jewish Ashkenazi and Iraqi individuals, and sporadically in non-Jews. Previous studies estimated that this is a founder mutation in Jewish mutation carriers that arose before the dispersion of Jews in the Diaspora ~2500 years ago. The aim of this study was to assess the haplotype in ethnically diverse 185delAG* BRCA1 mutation carriers, and to estimate the age at which the mutation arose. Ethnically diverse Jewish and non-Jewish 185delAG*BRCA1 mutation carriers and their relatives were genotyped using 15 microsatellite markers and three SNPs spanning 12.5 MB, encompassing the BRCA1 gene locus. Estimation of mutation age was based on a subset of 11 markers spanning a region of ~5 MB, using a previously developed algorithm applying the maximum likelihood method. Overall, 188 participants (154 carriers and 34 noncarriers) from 115 families were included: Ashkenazi, Iraq, Kuchin-Indians, Syria, Turkey, Iran, Tunisia, Bulgaria, non-Jewish English, non-Jewish Malaysian, and Hispanics. Haplotype analysis indicated that the 185delAG mutation arose 750-1500 years ago. In Ashkenazim, it is a founder mutation that arose 61 generations ago, and with a small group of founder mutations was introduced into the Hispanic population (conversos) ~650 years ago, and into the Iraqi-Jewish community ~450 years ago. The 185delAG mutation in the non-Jewish populations in Malaysia and the UK arose at least twice independently. We conclude that the 185delAG* BRCA1 mutation resides on a common haplotype among Ashkenazi Jews, and arose about 61 generations ago and arose independently at least twice in non-Jews.
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| 39. |
- Li, Liang, et al.
(författare)
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A Cosmological Fireball with 16% Gamma-Ray Radiative Efficiency
- 2023
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Ingår i: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8205 .- 2041-8213. ; 944:2
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Tidskriftsartikel (refereegranskat)abstract
- Gamma-ray bursts (GRBs) are the most powerful explosions in the universe. How efficiently the jet converts its energy to radiation is a long-standing problem, which is poorly constrained. The standard model invokes a relativistic fireball with a bright photosphere emission component. A definitive diagnosis of GRB radiation components and the measurement of GRB radiative efficiency require prompt emission and afterglow data, with high resolution and wide band coverage in time and energy. Here, we present a comprehensive temporal and spectral analysis of the TeV-emitting bright GRB 190114C. Its fluence is one of the highest for all the GRBs that have been detected so far, which allows us to perform a high-resolution study of the prompt emission spectral properties and their temporal evolutions, down to a timescale of about 0.1 s. We observe that each of the initial pulses has a thermal component contributing ∼20% of the total energy and that the corresponding temperature and inferred Lorentz factor of the photosphere evolve following broken power-law shapes. From the observation of the nonthermal spectra and the light curve, the onset of the afterglow corresponding to the deceleration of the fireball is considered to start at ∼6 s. By incorporating the thermal and nonthermal observations, as well as the photosphere and synchrotron radiative mechanisms, we can directly derive the fireball energy budget with little dependence on hypothetical parameters, measuring a ∼16% radiative efficiency for this GRB. With the fireball energy budget derived, the afterglow microphysics parameters can also be constrained directly from the data.
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| 40. |
- Liu, Cong, et al.
(författare)
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Ambient Particulate Air Pollution and Daily Mortality in 652 Cities
- 2019
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Ingår i: New England Journal of Medicine. - Waltham : Massachusetts Medical Society. - 0028-4793 .- 1533-4406. ; 381:8, s. 705-715
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The systematic evaluation of the results of time-series studies of air pollution is challenged by differences in model specification and publication bias.METHODS: We evaluated the associations of inhalable particulate matter (PM) with an aerodynamic diameter of 10 μm or less (PM10) and fine PM with an aerodynamic diameter of 2.5 μm or less (PM2.5) with daily all-cause, cardiovascular, and respiratory mortality across multiple countries or regions. Daily data on mortality and air pollution were collected from 652 cities in 24 countries or regions. We used overdispersed generalized additive models with random-effects meta-analysis to investigate the associations. Two-pollutant models were fitted to test the robustness of the associations. Concentration-response curves from each city were pooled to allow global estimates to be derived.RESULTS: On average, an increase of 10 μg per cubic meter in the 2-day moving average of PM10 concentration, which represents the average over the current and previous day, was associated with increases of 0.44% (95% confidence interval [CI], 0.39 to 0.50) in daily all-cause mortality, 0.36% (95% CI, 0.30 to 0.43) in daily cardiovascular mortality, and 0.47% (95% CI, 0.35 to 0.58) in daily respiratory mortality. The corresponding increases in daily mortality for the same change in PM2.5 concentration were 0.68% (95% CI, 0.59 to 0.77), 0.55% (95% CI, 0.45 to 0.66), and 0.74% (95% CI, 0.53 to 0.95). These associations remained significant after adjustment for gaseous pollutants. Associations were stronger in locations with lower annual mean PM concentrations and higher annual mean temperatures. The pooled concentration-response curves showed a consistent increase in daily mortality with increasing PM concentration, with steeper slopes at lower PM concentrations.CONCLUSIONS: Our data show independent associations between short-term exposure to PM10 and PM2.5 and daily all-cause, cardiovascular, and respiratory mortality in more than 600 cities across the globe. These data reinforce the evidence of a link between mortality and PM concentration established in regional and local studies. (Funded by the National Natural Science Foundation of China and others.).
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| 41. |
- Mueller, Christian P., et al.
(författare)
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The Cortical Neuroimmune Regulator TANK Affects Emotional Processing and Enhances Alcohol Drinking : A Translational Study
- 2019
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Ingår i: Cerebral Cortex. - : OXFORD UNIV PRESS INC. - 1047-3211 .- 1460-2199. ; 29:4, s. 1736-1751
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Tidskriftsartikel (refereegranskat)abstract
- Alcohol abuse is a major public health problem worldwide. Understanding the molecular mechanisms that control regular drinking may help to reduce hazards of alcohol consumption. While immunological mechanisms have been related to alcohol drinking, most studies reported changes in immune function that are secondary to alcohol use. In this report, we analyse how the gene "TRAF family member-associated NF-kappa B activator" (TANK) affects alcohol drinking behavior. Based on our recent discovery in a large GWAS dataset that suggested an association of TANK, SNP rs197273, with alcohol drinking, we report that SNP rs197273 in TANK is associated both with gene expression (P = 1.16 x 10(-19)) and regional methylation (P = 5.90 x 10(-25)). A tank knock out mouse model suggests a role of TANK in alcohol drinking, anxiety-related behavior, as well as alcohol exposure induced activation of insular cortex NF-kappa B. Functional and structural neuroimaging studies among up to 1896 adolescents reveal that TANK is involved in the control of brain activity in areas of aversive interoceptive processing, including the insular cortex, but not in areas related to reinforcement, reward processing or impulsiveness. Our findings suggest that the cortical neuroimmune regulator TANK is associated with enhanced aversive emotional processing that better protects from the establishment of alcohol drinking behavior.
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| 42. |
- Nepomuceno, Thales C., et al.
(författare)
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BRCA1 frameshift variants leading to extended incorrect protein C termini
- 2023
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Ingår i: Human Genetics and Genomics Advances. - : Elsevier. - 2666-2477. ; 4:4
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Tidskriftsartikel (refereegranskat)abstract
- Carriers of BRCA1 germline pathogenic variants are at substantially higher risk of developing breast and ovarian cancer than the general population. Accurate identification of at-risk individuals is crucial for risk stratification and the implementation of targeted preventive and therapeutic interventions. Despite significant progress in variant classification efforts, a sizable portion of reported BRCA1 variants remain as variants of uncertain clinical significance (VUSs). Variants leading to premature protein termination and loss of essential functional domains are typically classified as pathogenic. However, the impact of frameshift variants that result in an extended incorrect terminus is not clear. Using validated functional assays, we conducted a systematic functional assessment of 17 previously reported BRCA1 extended incorrect terminus variants (EITs) and concluded that 16 constitute loss-of-function variants. This suggests that most EITs are likely to be pathogenic. However, one variant, c.5578dup, displayed a protein expression level, affinity to known binding partners, and activity in transcription and homologous recombination assays comparable to the wild-type BRCA1 protein. Twenty-three additional carriers of c.5578dup were identified at a US clinical diagnostic lab and assessed using a family history likelihood model providing, in combination with the functional data, a likely benign interpretation. These results, consistent with family history data in the current study and available data from ClinVar, indicate that most, but not all, BRCA1 variants leading to an extended incorrect terminus constitute loss-of-function variants and underscore the need for comprehensive assessment of individual variants.
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| 43. |
- Paul, Dirk S., et al.
(författare)
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Increased DNA methylation variability in type 1 diabetes across three immune effector cell types
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- The incidence of type 1 diabetes (T1D) has substantially increased over the past decade, suggesting a role for non-genetic factors such as epigenetic mechanisms in disease development. Here we present an epigenome-wide association study across 406,365 CpGs in 52 monozygotic twin pairs discordant for T1D in three immune effector cell types. We observe a substantial enrichment of differentially variable CpG positions (DVPs) in T1D twins when compared with their healthy co-twins and when compared with healthy, unrelated individuals. These T1D-associated DVPs are found to be temporally stable and enriched at gene regulatory elements. Integration with cell type-specific gene regulatory circuits highlight pathways involved in immune cell metabolism and the cell cycle, including mTOR signalling. Evidence from cord blood of newborns who progress to overt T1D suggests that the DVPs likely emerge after birth. Our findings, based on 772 methylomes, implicate epigenetic changes that could contribute to disease pathogenesis in T1D.
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| 44. |
- Rajaraman, Preetha, et al.
(författare)
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Genome-wide association study of glioma and meta-analysis
- 2012
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Ingår i: Human Genetics. - : SPRINGER. - 0340-6717 .- 1432-1203. ; 131:12, s. 1877-1888
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Tidskriftsartikel (refereegranskat)abstract
- Gliomas account for approximately 80 % of all primary malignant brain tumors and, despite improvements in clinical care over the last 20 years, remain among the most lethal tumors, underscoring the need for gaining new insights that could translate into clinical advances. Recent genome-wide association studies (GWAS) have identified seven new susceptibility regions. We conducted a new independent GWAS of glioma using 1,856 cases and 4,955 controls (from 14 cohort studies, 3 case-control studies, and 1 population-based case-only study) and found evidence of strong replication for three of the seven previously reported associations at 20q13.33 (RTEL), 5p15.33 (TERT), and 9p21.3 (CDKN2BAS), and consistent association signals for the remaining four at 7p11.2 (EGFR both loci), 8q24.21 (CCDC26) and 11q23.3 (PHLDB1). The direction and magnitude of the signal were consistent for samples from cohort and case-control studies, but the strength of the association was more pronounced for loci rs6010620 (20q,13.33; RTEL) and rs2736100 (5p15.33, TERT) in cohort studies despite the smaller number of cases in this group, likely due to relatively more higher grade tumors being captured in the cohort studies. We further examined the 85 most promising single nucleotide polymorphism (SNP) markers identified in our study in three replication sets (5,015 cases and 11,601 controls), but no new markers reached genome-wide significance. Our findings suggest that larger studies focusing on novel approaches as well as specific tumor subtypes or subgroups will be required to identify additional common susceptibility loci for glioma risk.
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| 45. |
- Roy, Sushmita, et al.
(författare)
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Identification of functional elements and regulatory circuits by Drosophila modENCODE.
- 2010
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Ingår i: Science (New York, N.Y.). - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 330:6012, s. 1787-1797
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Tidskriftsartikel (refereegranskat)abstract
- To gain insight into how genomic information is translated into cellular and developmental programs, the Drosophila model organism Encyclopedia of DNA Elements (modENCODE) project is comprehensively mapping transcripts, histone modifications, chromosomal proteins, transcription factors, replication proteins and intermediates, and nucleosome properties across a developmental time course and in multiple cell lines. We have generated more than 700 data sets and discovered protein-coding, noncoding, RNA regulatory, replication, and chromatin elements, more than tripling the annotated portion of the Drosophila genome. Correlated activity patterns of these elements reveal a functional regulatory network, which predicts putative new functions for genes, reveals stage- and tissue-specific regulators, and enables gene-expression prediction. Our results provide a foundation for directed experimental and computational studies in Drosophila and related species and also a model for systematic data integration toward comprehensive genomic and functional annotation.
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| 46. |
- Sandholm, Niina, et al.
(författare)
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New susceptibility loci associated with kidney disease in type 1 diabetes
- 2012
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Ingår i: PLOS Genetics. - San Francisco, USA : Public Library of Science, PLOS. - 1553-7390 .- 1553-7404. ; 8:9, s. e1002921-
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Tidskriftsartikel (refereegranskat)abstract
- Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genomewide association studies (GWAS) of T1D DN comprising similar to 2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2 x 10(-8)) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0 x 10(-9)). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-beta 1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1 x 10(-7)), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.
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| 47. |
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| 48. |
- Sproviero, William, et al.
(författare)
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ATXN2 trinucleotide repeat length correlates with risk of ALS
- 2017
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 51, s. 178.e1-178.e9
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Tidskriftsartikel (refereegranskat)abstract
- We investigated a CAG trinucleotide repeat expansion in the ATXN2 gene in amyotrophic lateral sclerosis (ALS). Two new case-control studies, a British dataset of 1474 ALS cases and 567 controls, and a Dutch dataset of 1328 ALS cases and 691 controls were analyzed. In addition, to increase power, we systematically searched PubMed for case-control studies published after 1 August 2010 that investigated the association between ATXN2 intermediate repeats and ALS. We conducted a meta-analysis of the new and existing studies for the relative risks of ATXN2 intermediate repeat alleles of between 24 and 34 CAG trinucleotide repeats and ALS. There was an overall increased risk of ALS for those carrying intermediate sized trinucleotide repeat alleles (odds ratio 3.06 [95% confidence interval 2.37-3.94]; p = 6 × 10(-18)), with an exponential relationship between repeat length and ALS risk for alleles of 29-32 repeats (R(2) = 0.91, p = 0.0002). No relationship was seen for repeat length and age of onset or survival. In contrast to trinucleotide repeat diseases, intermediate ATXN2 trinucleotide repeat expansion in ALS does not predict age of onset but does predict disease risk.
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| 49. |
- Sung, Yun Ju, et al.
(författare)
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A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure
- 2019
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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 28:15, s. 2615-2633
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Tidskriftsartikel (refereegranskat)abstract
- Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene–smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene–smoking interaction analysis and 38 were newly identified (P < 5 × 10−8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.
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| 50. |
- Wang, Bing, et al.
(författare)
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Precisely Defined Conjugated Oligoelectrolytes for Biosensing and Therapeutics
- 2019
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Ingår i: Advanced Materials. - : WILEY-V C H VERLAG GMBH. - 0935-9648 .- 1521-4095. ; 31:22
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Forskningsöversikt (refereegranskat)abstract
- Conjugated oligoelectrolytes (COEs) are a relatively new class of synthetic organic molecules with, as of yet, untapped potential for use in organic optoelectronic devices and bioelectronic systems. COEs also offer a novel molecular approach to biosensing, bioimaging, and disease therapy. Substantial progress has been made in the past decade at the intersection of chemistry, materials science, and the biological sciences developing COEs and their polymer analogues, namely, conjugated polyelectrolytes (CPEs), into synthetic systems with biological and biomedical utility. CPEs have traditionally attracted more attention in arenas of sensing, imaging, and therapy. However, the precisely defined molecular structures and interactions of COEs offer potential key advantages over CPEs, including higher reliability and fluorescence quantum efficiency, larger diversity of subcellular targeting strategies, and improved selectivity to biomolecules. Here, the unique-and sometimes overlooked-properties of COEs are discussed and the noticeable progress in their use for biological sensing, imaging, and therapy is reviewed.
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