| 271. |
- McKay, James D., et al.
(författare)
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Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes
- 2017
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 49:7, s. 1126-1132
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Tidskriftsartikel (refereegranskat)abstract
- Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genomewide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.
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| 272. |
- Murashita, K, et al.
(författare)
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Leptin reduces Atlantic salmon growth through the central pro-opiomelanocortin pathway
- 2011
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Ingår i: Comparative Biochemistry and Physiology - Part A: Molecular & Integrative Physiology. - 1095-6433. ; 158:1, s. 79-86
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Tidskriftsartikel (refereegranskat)abstract
- Leptin (Lep) is a key factor for the energy homeostasis in mammals, but the available data of its role in teleosts are not conclusive. There are large sequence differences among mammalian and teleost Lep, both at the gene and protein level. Therefore, in order to characterize Lep function in fish, the use of species-specific Lep is crucial. In this study, the cDNA sequence of salmon leptin a1 (lepa1) was used to establish a production protocol for recombinant salmon LepA1 (rsLepA1) in Escherichia coli, that enabled a final yield of 1.7 mg pure protein L⁻¹ culture. The effects of 20-day administration of rsLepA1 on growth and brain neuroendocrine peptide gene expression [npy, cart, agrp (-1 and -2), pomc (-a1, -a2, -a2s, and -b)] were studied in juvenile, immature Atlantic salmon (96.5±2.1g) fed a commercial diet to satiation. Intraperitoneal osmotic pumps were used to deliver rsLepA1 at four different concentrations (calculated pumping rates were 0, 0.1, 1.0 and 10 ng g⁻¹ h⁻¹). In the highest dosage group (10 ng g⁻¹ h⁻¹), the growth rate was significantly reduced, and pomc-a1 gene expression was higher than in controls. The results support the lipostatic hypothesis and suggest that sLepA1 reduces growth in Atlantic salmon by affecting food intake through the central pro-opiomelanocortin pathway.
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| 273. |
- Nik-Zainal, Serena, et al.
(författare)
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Landscape of somatic mutations in 560 breast cancer whole-genome sequences
- 2016
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 534:7605, s. 47-54
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Tidskriftsartikel (refereegranskat)abstract
- We analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement signatures. Three rearrangement signatures, characterized by tandem duplications or deletions, appear associated with defective homologous-recombination-based DNA repair: one with deficient BRCA1 function, another with deficient BRCA1 or BRCA2 function, the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operating, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer.
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| 274. |
- Oei, Ling, et al.
(författare)
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A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus
- 2014
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Ingår i: Journal of Medical Genetics. - : BMJ Publishing Group. - 0022-2593 .- 1468-6244. ; 51:2, s. 122-131
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Osteoporosis is a systemic skeletal disease characterised by reduced bone mineral density and increased susceptibility to fracture; these traits are highly heritable. Both common and rare copy number variants (CNVs) potentially affect the function of genes and may influence disease risk.AIM: To identify CNVs associated with osteoporotic bone fracture risk.METHOD: We performed a genome-wide CNV association study in 5178 individuals from a prospective cohort in the Netherlands, including 809 osteoporotic fracture cases, and performed in silico lookups and de novo genotyping to replicate in several independent studies.RESULTS: A rare (population prevalence 0.14%, 95% CI 0.03% to 0.24%) 210 kb deletion located on chromosome 6p25.1 was associated with the risk of fracture (OR 32.58, 95% CI 3.95 to 1488.89; p=8.69×10(-5)). We performed an in silico meta-analysis in four studies with CNV microarray data and the association with fracture risk was replicated (OR 3.11, 95% CI 1.01 to 8.22; p=0.02). The prevalence of this deletion showed geographic diversity, being absent in additional samples from Australia, Canada, Poland, Iceland, Denmark, and Sweden, but present in the Netherlands (0.34%), Spain (0.33%), USA (0.23%), England (0.15%), Scotland (0.10%), and Ireland (0.06%), with insufficient evidence for association with fracture risk.CONCLUSIONS: These results suggest that deletions in the 6p25.1 locus may predispose to higher risk of fracture in a subset of populations of European origin; larger and geographically restricted studies will be needed to confirm this regional association. This is a first step towards the evaluation of the role of rare CNVs in osteoporosis.
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| 275. |
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| 276. |
- Olafsdottir, Eydis, et al.
(författare)
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Early detection of type 2 diabetes mellitus and screening for retinopathy are associated with reduced prevalence and severity of retinopathy
- 2016
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Ingår i: Acta Ophthalmologica. - Hoboken, USA : Wiley-Blackwell Publishing Inc.. - 1755-375X .- 1755-3768. ; 94:3, s. 232-239
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To explore whether the prevalence and severity of retinopathy differ in diabetes cohorts diagnosed through screening as compared with conventional health care.Methods: A total of 257 diabetes patients, 151 detected through screening and 106 through conventional clinical care, were included. Retinopathy was evaluated by fundus photography. The modified Airlie House adaptation of the Early Treatment Retinopathy Study protocol was used to grade the photographs. Averages of clinically collected fasting blood glucose (FBG), blood pressure and body mass index values were compiled from diabetes diagnosis until the eye examination. Blood chemistry, smoking habits and peripheral neuropathy were assessed at the time of the eye examination.Results: Among the screening-detected patients, 22% had retinopathy as compared to 51% among those clinically detected (p < 0.0001). In a multivariate analysis, patients with retinopathy were more likely to have increased average FBG (OR 1.42, 95% CI 1.19-1.70 per mmol/l) and peripheral neuropathy (OR 2.75, 95% CI 1.40-5.43), but less likely to have screening-detected diabetes (OR 0.31, 95% CI 0.17-0.57). Similar results were found using increasing severity grade of retinopathy as outcome. The cumulative retinopathy prevalence for the screening-detected diabetes cohort as compared with the clinically diagnosed cohort was significantly lower from 10 years' follow-up and onwards (p = 0.0002).Conclusions: Among patients with screening-detected diabetes, the prevalence of retinopathy and increasing severity of retinopathy were significantly lower than among those who had their diabetes diagnosed through conventional care, even when other risk factors for retinopathy such as duration, hyperglycaemia and blood pressure were considered. Early detection of diabetes reduces prediagnostic time spent with hyperglycaemia. In combination with early and regular screening for retinopathy, more effective prevention against retinopathy can be provided.
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| 277. |
- Olafsdottir, Eydis, et al.
(författare)
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The prevalence of cataract in a population with and without type 2 diabetes mellitus
- 2012
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Ingår i: Acta Ophthalmologica. - : Wiley. - 1755-375X .- 1755-3768. ; 90:4, s. 334-340
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To evaluate the prevalence and risk factors of lens opacities in a geographically defined population of subjects with type 2 diabetes mellitus compared with a control population.Methods: Subjects in the community of Laxa with a diagnosis of type 2 diabetes mellitus (n = 275) and a control group (n = 256) participated in the study. Lens opacities were graded with Lens Opacities Classification System II in all participants. Lens Opacities Classification System score 2 was considered as significant lens opacity. Anthropometric and blood chemistry data were collected for all participants in connection with the eye examination. For the diabetic population, yearly updated information on glucose control, blood pressure and body mass index was available through medical records from diabetes diagnosis until the time of the eye examination.Results: The prevalence of significant cortical, posterior subcapsular and nuclear cataract was 65.5%, 42.5% and 48.0%, respectively, in the type 2 diabetes population in Laxa. In logistic regression analyses, all types of lens opacities were strongly associated with age (p < 0.0001). Cortical lens opacity was also associated with a diagnosis of diabetes (p < 0.0001), posterior subcapsular lens opacity with HbA1c (p < 0.0001) and nuclear lens opacity with female gender and higher heart rate (both p = 0.0004). In the diabetic population, all types of cataract were likewise strongly associated with age (p < 0.0001), posterior subcapsular cataract with HbA1c (p = 0.0032), nuclear cataract with female gender (p = 0.0002) and higher heart rate (p = 0.0008).Conclusions: Our study shows that cortical cataract is associated with diabetes mellitus, not necessarily defined by glucose control, whereas posterior subcapsular cataract is associated with glucose levels. Nuclear cataract is not associated with diabetes mellitus, but is more frequent in women and is also associated with higher heart rate.
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| 278. |
- Olafsdottir, Eydis, et al.
(författare)
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The prevalence of retinopathy in subjects with and without type 2 diabetes mellitus
- 2014
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Ingår i: Acta Ophthalmologica. - : Wiley. - 1755-375X .- 1755-3768. ; 92:2, s. 133-137
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Tidskriftsartikel (refereegranskat)abstract
- Abstract. Purpose: To evaluate the prevalence of and risk factors for, retinopathy in a geographically defined population with type 2 diabetes mellitus compared with a control group of subjects without diabetes, matched by age, sex and residence in order to find the retinopathy attributable to type 2 diabetes. Methods: The study populations are, on one hand, a prevalence cohort of subjects with type 2 diabetes resident in the community of Laxa, Sweden, and on the other a control group, matched by age, gender and residence with those with a diagnosis of type 2 diabetes mellitus. Retinopathy was graded from fundus photographs using a modification of the Early Treatment Retinopathy Study (ETDRS) adaptation of the modified Airlie House classification of diabetic retinopathy (DR). Results: Any retinopathy was found in 34.6% in the type 2 diabetes cohort and in 8.8% in the control group without diabetes. Among the diabetic patients, any retinopathy was significantly associated with duration of diabetes (p = 0.0001), HbA1c (p = 0.0056), systolic blood pressure (p = 0.0091) and lower serum cholesterol (p = 0.0197) in multivariate logistic regression analyses. Having retinopathy in the control group was associated only with systolic blood pressure (p = 0.0014) in logistic regression analysis. Conclusions: The prevalence of retinopathy among patients with type 2 diabetes in Laxa, Sweden, was similar or somewhat lower compared with other studies in the Nordic countries. The prevalence of retinopathy in a control group without diabetes equalled numbers from population studies worldwide. Our study indicates that the retinopathy that can be attributed to hyperglycaemia in the diabetic state is less common than is usually accounted for. A considerable fraction of retinopathy in subjects with diabetes may instead be due to other factors such as hypertension and should thus be treated correspondingly.
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| 279. |
- Olafsdottir, Eydis, et al.
(författare)
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Visual acuity in a population with regular screening for type 2 diabetes mellitus and eye disease
- 2007
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Ingår i: Acta Ophthalmologica Scandinavica. - : Wiley. - 1395-3907 .- 1600-0420. ; 85:1, s. 40-45
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Regular screening for both diabetes mellitus and diabetic eye disease should be the gold standard in preventing diabetic blindness. In the community of Laxå, County of Örebro, Sweden, such screening has been carried out since 1983. We evaluate visual impairment and blindness in this population. Methods: All persons in the community of Laxå with a diagnosis of type 2 diabetes mellitus (n = 276) participated in the study. An age- and gender-matched control group (n = 259) was assembled. Best corrected visual acuity (BCVA) was tested in all participants, and a detailed eye examination performed by an ophthalmologist. Results: No significant statistical differences were seen between the diabetes and control groups regarding visual acuity (VA). In all, 2.9% of the diabetes patients and 1.2% of the controls had BCVA ≤ 0.1. Only one person in the diabetes group was blind as a result of diabetic retinopathy. In both groups the leading cause of blindness was age-related macular degeneration. In a logistic regression analysis we found that in both the diabetes and the control populations, increasing age was related to worsening BCVA (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.10–1.16 versus OR 1.16, 95% CI 1.13–1.19), as was female gender in the diabetes group only (OR 2.73, 95% CI 1.69–4.40). Conclusions: In a population that is carefully screened for diabetes mellitus and provided with regular screening for diabetic retinopathy, the loss of vision from diabetic retinopathy is uncommon.
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| 280. |
- Perry, John R. B., et al.
(författare)
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Stratifying Type 2 Diabetes Cases by BMI Identifies Genetic Risk Variants in LAMA1 and Enrichment for Risk Variants in Lean Compared to Obese Cases
- 2012
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 8:5
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Tidskriftsartikel (refereegranskat)abstract
- Common diseases such as type 2 diabetes are phenotypically heterogeneous. Obesity is a major risk factor for type 2 diabetes, but patients vary appreciably in body mass index. We hypothesized that the genetic predisposition to the disease may be different in lean (BMI<25 Kg/m(2)) compared to obese cases (BMI >= 30 Kg/m(2)). We performed two case-control genome-wide studies using two accepted cut-offs for defining individuals as overweight or obese. We used 2,112 lean type 2 diabetes cases (BMI<25 kg/m(2)) or 4,123 obese cases (BMI >= 30 kg/m(2)), and 54,412 un-stratified controls. Replication was performed in 2,881 lean cases or 8,702 obese cases, and 18,957 un-stratified controls. To assess the effects of known signals, we tested the individual and combined effects of SNPs representing 36 type 2 diabetes loci. After combining data from discovery and replication datasets, we identified two signals not previously reported in Europeans. A variant (rs8090011) in the LAMA1 gene was associated with type 2 diabetes in lean cases (P = 8.4610 29, OR = 1.13 [95% CI 1.09-1.18]), and this association was stronger than that in obese cases (P = 0.04, OR = 1.03 [95% CI 1.00-1.06]). A variant in HMG20A-previously identified in South Asians but not Europeans-was associated with type 2 diabetes in obese cases (P = 1.3 x 10(-8), OR= 1.11 [95% CI 1.07-1.15]), although this association was not significantly stronger than that in lean cases (P = 0.02, OR = 1.09 [95% CI 1.02-1.17]). For 36 known type 2 diabetes loci, 29 had a larger odds ratio in the lean compared to obese (binomial P = 0.0002). In the lean analysis, we observed a weighted per-risk allele OR = 1.13 [95% CI 1.10-1.17], P = 3.2 x 10(-14). This was larger than the same model fitted in the obese analysis where the OR = 1.06 [95% CI 1.05-1.08], P = 2.2 x 10(-16). This study provides evidence that stratification of type 2 diabetes cases by BMI may help identify additional risk variants and that lean cases may have a stronger genetic predisposition to type 2 diabetes.
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