| 61. |
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| 62. |
- Sawcer, Stephen, et al.
(författare)
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Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
- 2011
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 476:7359, s. 214-219
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
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| 63. |
- Shu, Xiang, et al.
(författare)
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Associations of obesity and circulating insulin and glucose with breast cancer risk : a Mendelian randomization analysis
- 2019
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Ingår i: International Journal of Epidemiology. - : OXFORD UNIV PRESS. - 0300-5771 .- 1464-3685. ; 48:3, s. 795-806
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Tidskriftsartikel (refereegranskat)abstract
- Background: In addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the development of this common malignancy. Findings from previous studies, however, have been inconsistent, and the nature of the associations is unclear. Methods: We conducted Mendelian randomization analyses to evaluate the association of breast cancer risk, using genetic instruments, with fasting insulin, fasting glucose, 2-h glucose, body mass index (BMI) and BMI-adjusted waist-hip-ratio (WHRadj BMI). We first confirmed the association of these instruments with type 2 diabetes risk in a large diabetes genome-wide association study consortium. We then investigated their associations with breast cancer risk using individual-level data obtained from 98 842 cases and 83 464 controls of European descent in the Breast Cancer Association Consortium. Results: All sets of instruments were associated with risk of type 2 diabetes. Associations with breast cancer risk were found for genetically predicted fasting insulin [odds ratio (OR) = 1.71 per standard deviation (SD) increase, 95% confidence interval (CI) = 1.26-2.31, p = 5.09 x 10(-4)], 2-h glucose (OR = 1.80 per SD increase, 95% CI = 1.3 0-2.49, p = 4.02 x 10(-4)), BMI (OR = 0.70 per 5-unit increase, 95% CI = 0.65-0.76, p = 5.05 x 10(-19)) and WHRadj BMI (OR = 0.85, 95% CI = 0.79-0.91, p = 9.22 x 10(-6)). Stratified analyses showed that genetically predicted fasting insulin was more closely related to risk of estrogen-receptor [ER]-positive cancer, whereas the associations with instruments of 2h glucose, BMI and WHRadj BMI were consistent regardless of age, menopausal status, estrogen receptor status and family history of breast cancer. Conclusions: We confirmed the previously reported inverse association of genetically predicted BMI with breast cancer risk, and showed a positive association of genetically predicted fasting insulin and 2-h glucose and an inverse association of WHRadj BMI with breast cancer risk. Our study suggests that genetically determined obesity and glucose/insulin-related traits have an important role in the aetiology of breast cancer.
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| 64. |
- Snell, Per, et al.
(författare)
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Characterisation of Grains and Flour Fractions from Field Grown Transgenic Oil-Accumulating Wheat Expressing Oat WRI1
- 2022
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Ingår i: Plants. - : MDPI AG. - 2223-7747. ; 11:7
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Tidskriftsartikel (refereegranskat)abstract
- Wheat (Triticum aestivum L.) is one of the major staple crops in the world and is used to prepare a range of foods. The development of new varieties with wider variation in grain composition could broaden their use. We characterized grains and flours from oil-accumulating transgenic wheat expressing the oat (Avena sativa L.) endosperm WRINKLED1 (AsWRI1) grown under field conditions. Lipid and starch accumulation was determined in developing caryopses of AsWRI1-wheat and X-ray microtomography was used to study grain morphology. The developing caryopses of AsWRI1-wheat grains had increased triacylglycerol content and decreased starch content compared to the control. Mature AsWRI1-wheat grains also had reduced weight, were wrinkled and had a shrunken endosperm and X-ray tomography revealed that the proportion of endosperm was decreased while that of the aleurone was increased. Grains were milled to produce two white flours and one bran fraction. Mineral and lipid analyses showed that the flour fractions from the AsWRI1-wheat were contaminated with bran, due to the effects of the changed morphology on milling. This study gives a detailed analysis of grains from field grown transgenic wheat that expresses a gene that plays a central regulatory role in carbon allocation and significantly affects grain composition.
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| 65. |
- Speliotes, Elizabeth K., et al.
(författare)
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Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 937-948
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ~2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10−8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
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| 66. |
- Ståhl, H., et al.
(författare)
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Factors influencing organic carbon recycling and burial in Skagerrak sediments
- 2004
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Ingår i: Journal of Marine Research. - : Journal of Marine Research/Yale. - 0022-2402 .- 1543-9542. ; 62:6, s. 867-907
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Tidskriftsartikel (refereegranskat)abstract
- Different factors influencing recycling and burial rates of organic carbon (OC) were investigated in the continental margin sediments of the Skagerrak (NE North Sea). Two different areas, one in the southern and one in the northeastern part of the Skagerrak were visited shortly after a spring bloom (March 1999) and in late summer (August 2000). Results suggested that: (1) Organic carbon oxidation rates (C-ox) (2.2-18 mmol Cm-2 d(-1)) were generally larger than the O-2 uptake rates (1.9-25 mmol m(-2) d(-1)). Both rates were measured in situ using a benthic lander. A mean apparent respiration ratio (C-ox:O-2corr) of 1.3 +/- 0.5 was found, indicating some long-term burial of reduced inorganic substances in these sediments. Measured O-2, fluxes increased linearly with increasing C-ox rates during the late summer cruise but not on the, early spring cruise, indicating a temporal uncoupling of anaerobic mineralization and reoxidation of reduced substances. (2) Dissolved organic carbon (DOC) fluxes (0.2-1.0 mmol Cm-2 d(-1)) constituted 3-10% of the C-ox rates and were positively correlated with the latter, implying that net DOC production rates were proportional to the overall sediment OC remineralization rates. (3) Chlorophyll a (Chl-a) concentrations in the sediment were significantly higher in early spring compared to late summer. The measured C-ox rates, but not O-2 fluxes, showed a strong positive correlation with the Chl-a inventories in the top 3 cm of the sediment. (4) Although no relationship was found between the benthic fluxes and the macrofaunal biomass in the chambers, total in situ measured dissolved inorganic carbon (C-T) fluxes were 1-5.4 times higher than diffusive mediated C-T fluxes, indicating that macrofauna have a significant impact on benthic exchange rates of OC remineralization products in Skagerrak sediments. (5) OC burial fluxes were generally higher in northeastern Skagerrak than in the southern part. The same pattern was observed for burial efficiencies, with annual means of similar to62% and similar to43% for the two areas respectively. (6) On a basin-wide scale, there was a significant positive linear correlation between the burial efficiencies and sediment accumulation rates. (7) The calculated particulate organic carbon (POC) deposition, from benthic flux and burial measurements, was only 24-78% of the sediment trap measured POC deposition, indicating a strong near-bottom lateral transport and resuspension of POC. (8) A larger fraction of the laterally advected material of lower quality seemed to settle in the northeastern Skagerrak rather than in the southern Skagerrak. (9) Skagerrak sediments, especially in the northeastern part, act as an efficient net sink for organic carbon, even in a global continental margin context.
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| 67. |
- Viktorsson, Lena, 1980, et al.
(författare)
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Recycling and burial of phosphorus in sediments of an anoxic fjord - The By Fjord, western Sweden
- 2013
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Ingår i: Journal of Marine Research. - : Journal of Marine Research/Yale. - 0022-2402 .- 1543-9542. ; 71:5, s. 351-374
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Tidskriftsartikel (refereegranskat)abstract
- Recycling and burial of sediment phosphorus were studied in the By Fjord, western Sweden, during the years 2009 to 2010 using autonomous benthic landers and sediment sampling. The By Fjord is a small fjord with a shallow sill at its narrow mouth, which limits water exchange of the fjord’s basin water. The water in the basin is exchanged only every 3 to 5 years and the water below sill level is anoxic or sulfidic between water renewals. Five sites were examined in the By Fjord; three shallow sites above the sill level with oxic bottom waters and two deeper sites with anoxic bottom waters. Contents of sediment organic carbon and total nitrogen were higher at deep stations when compared to shallow stations, whereas the contents of sediment inorganic P was higher, and sediment organic P generally lower, at shallow than at deep stations both in surficial and buried sediment. One shallow oxic site and one deep anoxic site were also examined in the adjacent Koljo Fjord having similar characteristics as the By Fjord. In situ measurements of benthic fluxes of dissolved inorganic phosphorus (DIP) showed that the fluxes from sediments with oxic overlying water (0.05–0.23 mmol m−2 d−1) were much lower than fluxes from sediments with anoxic overlying water (1.25–2.26 mmol m−2 d−1). The DIP flux increased with increasing flux of dissolved inorganic carbon (DIC) not only at anoxic but also at oxic bottoms, which is different from observations in brackish water environments. The average ratio between the DIC and DIP fluxes at oxic bottoms was almost 10 times higher than the Redfield C:P ratio indicating partial immobilization of P in oxic sediments. In contrast, the C:P ratio in fluxes was on average 1.5 times lower than Redfield at the anoxic bottoms. The benthic fluxes from anoxic bottoms were P rich not only in relation to C, but also to N. The low C:P flux ratio at anoxic sites coincided with a ≈ 2.5 times higher than Redfield C:P ratio of organic matter in the sediment solid phase clearly suggesting preferential regeneration of P at anoxic bottoms. Burial of inorganic P was higher than organic P burial at both anoxic and oxic sites; the former made up 59 to 60% of the total P burial at the deep anoxic stations, and 80% at the main shallow oxic station. The burial efficiency for organic P at anoxic bottoms was estimated to be only 1 to 3%, which indicates extremely efficient recycling of deposited organic P under anoxic conditions in this fjord environment.
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| 68. |
- Wain, Louise V, et al.
(författare)
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Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets.
- 2017
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 49:3, s. 416-425
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Tidskriftsartikel (refereegranskat)abstract
- Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function and is the third leading cause of death globally. Through genome-wide association discovery in 48,943 individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 individuals, we increased the yield of independent signals for lung function from 54 to 97. A genetic risk score was associated with COPD susceptibility (odds ratio per 1 s.d. of the risk score (∼6 alleles) (95% confidence interval) = 1.24 (1.20-1.27), P = 5.05 × 10(-49)), and we observed a 3.7-fold difference in COPD risk between individuals in the highest and lowest genetic risk score deciles in UK Biobank. The 97 signals show enrichment in genes for development, elastic fibers and epigenetic regulation pathways. We highlight targets for drugs and compounds in development for COPD and asthma (genes in the inositol phosphate metabolism pathway and CHRM3) and describe targets for potential drug repositioning from other clinical indications.
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| 69. |
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| 70. |
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