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- Albrechtsen, A., et al.
(författare)
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Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes
- 2013
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 56:2, s. 298-310
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Tidskriftsartikel (refereegranskat)abstract
- Human complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) > 1% with common metabolic phenotypes. The study comprised three stages. We performed medium-depth (8x) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI > 27.5 kg/m(2) and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p < 0.05) with case-control status, from four selected annotation categories or from loci reported to associate with metabolic traits. These variants were genotyped in 15,989 Danes to search for association with 12 metabolic phenotypes (stage 2). In stage 3, polymorphisms showing potential associations were genotyped in a further 63,896 Europeans. Exome sequencing identified 70,182 polymorphisms with MAF > 1%. In stage 2 we identified 51 potential associations with one or more of eight metabolic phenotypes covered by 45 unique polymorphisms. In meta-analyses of stage 2 and stage 3 results, we demonstrated robust associations for coding polymorphisms in CD300LG (fasting HDL-cholesterol: MAF 3.5%, p = 8.5 x 10(-14)), COBLL1 (type 2 diabetes: MAF 12.5%, OR 0.88, p = 1.2 x 10(-11)) and MACF1 (type 2 diabetes: MAF 23.4%, OR 1.10, p = 8.2 x 10(-10)). We applied exome sequencing as a basis for finding genetic determinants of metabolic traits and show the existence of low-frequency and common coding polymorphisms with impact on common metabolic traits. Based on our study, coding polymorphisms with MAF above 1% do not seem to have particularly high effect sizes on the measured metabolic traits.
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- Palmer, Nicholette D, et al.
(författare)
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A genome-wide association search for type 2 diabetes genes in African Americans.
- 2012
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Ingår i: PloS one. - San Francisco : Public Library of Science (PLoS). - 1932-6203. ; 7:1, s. e29202-
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Tidskriftsartikel (refereegranskat)abstract
- African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
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- Backeström, A., et al.
(författare)
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Glucose metabolism and cognitive dysfunction
- 2010
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Ingår i: Abstracts of the EASD, Stockholm 2010. - : Springer Science and Business Media LLC. ; , s. S292-S292
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Konferensbidrag (refereegranskat)abstract
- Background and aims: The association between type 2 diabetes and different forms of cognitive impairment is well established. The mechanism behind the association is however still unrevealed. We have recently reported that raised blood glucose levels were associated to impairment in episodic memory, the memory function first affected in the progress to dementia. However, patients with type 2 diabetes have not only elevated levels of blood glucose, but also increased levels of insulin because of insulin resistance. It has been suggested that insulin itself might have a negative effect on cognitive function and memory. Diabetes is associated with a long standing hyperglycaemia but also with hypertension and hyperlipideima, leading to micro and macro vascular disease. Thus, our aim was to study whether insulin affects episodic memory independently of glucose in a nondiabetic adult population. Materials and methods: We linked and matched two large population based data sets in Sweden, the Betula study and the Västerbotten Intervention Program. We identified 364 (F/M 207/157, mean age 50.5 ±8.0 years) nondiabetic subjects, free from dementia, who had participated in the two surveys within six months. The memory test included testing of episodic memory. We transformed the results using the mean values and standard deviation from the youngest age group to compute a composite z-score (subjects’ value minus mean score in the 40-year-old group divided by SD). Fasting plasma insulin (FPI) and glucose (FPG) were analyzed with standard methods. Results: Women had higher levels of episodic memory (mean z-score -0.06, SD 0.54) compared to men (mean z-score -0.36, SD 0.51, p<0.001). Given the sex difference in the outcome variable we stratified for sex. In a univariate linear regression both FPG (B -0.274, SE 0.068, Beta -0.271, p<0.001) and FPI (B -0.389, SE 0.131, Beta -0.204, p=0.003) were significantly associated with episodic memory in women but not in men. FPG, but not FPI, remained significantly associated with episodic memory after adjustment for hypertension, total P-cholesterol, bodymass index, educational level, depression, smoking and cardiovascular disease ( FPG: B -0.218, SE 0.070, Beta -0.220, p=0.002; FPI: B -0.232, SE 0.149, Beta -0.127, p=n.s.), when FPG and FPI were analyzed separately. Entering both FPG and FPI into the regression model did not attenuate the association between FPG and episodic memory (FPG: B -0.204, SE 0.071, Beta -0.206, p=0.005). Conclusion: We conclude that an increase in plasma glucose, but not plasma insulin, is associated with impairment in episodic memory in women. This could be explained by a negative effect on the hippocampus caused by raised plasma glucose levels.
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- Fhärm, E, et al.
(författare)
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Time trends in absolute and modifiable coronary heart disease risk in patients with Type 2 diabetes in the Swedish National Diabetes Register (NDR) 2003-2008
- 2012
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Ingår i: Diabetic Medicine. - : Wiley. - 0742-3071 .- 1464-5491. ; 29:2, s. 198-206
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Tidskriftsartikel (refereegranskat)abstract
- Aims: The aim was to evaluate treatment goal achievements early in the course of Type 2 diabetes, and their effect on 10-year risk of coronary heart disease in patients receiving usual care. Methods: Assessment of risk factor control 3 years after diagnosis in patients with Type 2 diabetes with no previous coronary heart disease included from the Swedish National Diabetes Register; a total of 19 382 patients (mean age 58 years) in cross-sectional surveys from 2003 to 2008, and a subgroup of 4293 patients followed individually from year of diagnosis to follow-up after a mean 2.6 years. Estimation of absolute 10-year risk of coronary heart disease using the UK Prospective Diabetes Study risk engine, and modifiable 10-year risk defined as percentage excess risk above patients with 'normal' risk factor values. Results: Treatment goals for HbA(1c) , blood pressure, total and LDL cholesterol were achieved in 78.4, 65.5, 55.6% and 61.0%, respectively, in the cross-sectional survey in 2008, following a trend of generally improved control. In the individually followed patients in the subgroup, mean absolute 10-year coronary heart disease risk increased from 13.7% (men/women 16.9/9.5%) to 14.2 (men/women 17.6/9.6%) (P < 0.001) from year of diagnosis to follow-up after 2.6 years, while mean modifiable risk decreased from 37.7% (men/women 28.6/49.9%) to 19.1% (13.2/26.9%) (P < 0.001 in all). Conclusions: A high achievement of treatment goals and a low mean modifiable 10-year coronary heart disease risk was found at the 3-year follow-up, both in the cross-sectional survey in 2008 and in patients individually followed since diagnosis. This indicates the feasibility and significance of early multifactorial risk factor treatment.
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- Langenberg, C., et al.
(författare)
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Design and cohort description of the InterAct Project : an examination of the interaction of genetic and lifestyle factors on the incidence of type 2 diabetes in the EPIC Study
- 2011
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Ingår i: Diabetologia. - : Springer. - 0012-186X .- 1432-0428. ; 54:9, s. 2272-2282
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Tidskriftsartikel (refereegranskat)abstract
- Studying gene-lifestyle interaction may help to identify lifestyle factors that modify genetic susceptibility and uncover genetic loci exerting important subgroup effects. Adequately powered studies with prospective, unbiased, standardised assessment of key behavioural factors for gene-lifestyle studies are lacking. This case-cohort study aims to investigate how genetic and potentially modifiable lifestyle and behavioural factors, particularly diet and physical activity, interact in their influence on the risk of developing type 2 diabetes. Incident cases of type 2 diabetes occurring in European Prospective Investigation into Cancer and Nutrition (EPIC) cohorts between 1991 and 2007 from eight of the ten EPIC countries were ascertained and verified. Prentice-weighted Cox regression and random-effects meta-analyses were used to investigate differences in diabetes incidence by age and sex. A total of 12,403 verified incident cases of type 2 diabetes occurred during 3.99 million person-years of follow-up of 340,234 EPIC participants eligible for InterAct. We defined a centre-stratified subcohort of 16,154 individuals for comparative analyses. Individuals with incident diabetes who were randomly selected into the subcohort (n = 778) were included as cases in the analyses. All prevalent diabetes cases were excluded from the study. InterAct cases were followed-up for an average of 6.9 years; 49.7% were men. Mean baseline age and age at diagnosis were 55.6 and 62.5 years, mean BMI and waist circumference values were 29.4 kg/m(2) and 102.7 cm in men, and 30.1 kg/m(2) and 92.8 cm in women, respectively. Risk of type 2 diabetes increased linearly with age, with an overall HR of 1.56 (95% CI 1.48-1.64) for a 10 year age difference, adjusted for sex. A male excess in the risk of incident diabetes was consistently observed across all countries, with a pooled HR of 1.51 (95% CI 1.39-1.64), adjusted for age. InterAct is a large, well-powered, prospective study that will inform our understanding of the interplay between genes and lifestyle factors on the risk of type 2 diabetes development.
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