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- Munn-Chernoff, M. A., et al.
(författare)
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Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies
- 2021
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Ingår i: Addiction Biology. - : Wiley. - 1355-6215 .- 1369-1600. ; 26:1
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Tidskriftsartikel (refereegranskat)abstract
- Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [r(g)], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from similar to 2400 to similar to 537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (r(g) = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (r(g) = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (r(g) = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (r(gs) = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors.
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| 2. |
- de Rojas, I., et al.
(författare)
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Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease. © 2021, The Author(s).
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| 6. |
- Bellenguez, C, et al.
(författare)
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New insights into the genetic etiology of Alzheimer's disease and related dementias
- 2022
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:4, s. 412-436
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Tidskriftsartikel (refereegranskat)abstract
- Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.
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| 8. |
- Barker, A., et al.
(författare)
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Age-dependent decline of beta-cell function in type 1 diabetes after diagnosis: a multi-centre longitudinal study
- 2014
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Ingår i: Diabetes, obesity and metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 16:3, s. 262-267
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Tidskriftsartikel (refereegranskat)abstract
- AimsC-peptide secretion is currently the only available clinical biomarker to measure residual -cell function in type 1 diabetes. However, the natural history of C-peptide decline after diagnosis can vary considerably dependent upon several variables. We investigated the shape of C-peptide decline over time from type 1 diabetes onset in relation to age at diagnosis, haemoglobin A1c (HbA1c) levels and insulin dose. MethodsWe analysed data from 3929 type 1 diabetes patients recruited from seven European centres representing all age groups at disease onset (childhood, adolescence and adulthood). The influence of the age at onset on -cell function was investigated in a longitudinal analysis at diagnosis and up to 5-years follow-up. ResultsFasting C-peptide (FCP) data at diagnosis were available in 3668 patients stratified according to age at diagnosis in four groups (less than5years, n=344; greater than5yearsless than10years, n=668; greater than10yearsless than18years, n=991; greater than18years, n=1655). FCP levels were positively correlated with age (pless than0.001); the subsequent decline in FCP over time was log-linear with a greater decline rate in younger age groups (pless than0.0001). ConclusionsThis study reveals a positive correlation between age at diagnosis of type 1 diabetes and FCP with a more rapid decline of -cell function in the very young patients. These data can inform the design of clinical trials using C-peptide values as an end-point for the effect of a given treatment.
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| 10. |
- Dormandy, J. A., et al.
(författare)
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Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial
- 2005
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Ingår i: Lancet. - 1474-547X. ; 366:9493, s. 1279-89
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Patients with type 2 diabetes are at high risk of fatal and non-fatal myocardial infarction and stroke. There is indirect evidence that agonists of peroxisome proliferator-activated receptor gamma (PPAR gamma) could reduce macrovascular complications. Our aim, therefore, was to ascertain whether pioglitazone reduces macrovascular morbidity and mortality in high-risk patients with type 2 diabetes. METHODS: We did a prospective, randomised controlled trial in 5238 patients with type 2 diabetes who had evidence of macrovascular disease. We recruited patients from primary-care practices and hospitals. We assigned patients to oral pioglitazone titrated from 15 mg to 45 mg (n=2605) or matching placebo (n=2633), to be taken in addition to their glucose-lowering drugs and other medications. Our primary endpoint was the composite of all-cause mortality, non fatal myocardial infarction (including silent myocardial infarction), stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN NCT00174993. FINDINGS: Two patients were lost to follow-up, but were included in analyses. The average time of observation was 34.5 months. 514 of 2605 patients in the pioglitazone group and 572 of 2633 patients in the placebo group had at least one event in the primary composite endpoint (HR 0.90, 95% CI 0.80-1.02, p=0.095). The main secondary endpoint was the composite of all-cause mortality, non-fatal myocardial infarction, and stroke. 301 patients in the pioglitazone group and 358 in the placebo group reached this endpoint (0.84, 0.72-0.98, p=0.027). Overall safety and tolerability was good with no change in the safety profile of pioglitazone identified. 6% (149 of 2065) and 4% (108 of 2633) of those in the pioglitazone and placebo groups, respectively, were admitted to hospital with heart failure; mortality rates from heart failure did not differ between groups. INTERPRETATION: Pioglitazone reduces the composite of all-cause mortality, non-fatal myocardial infarction, and stroke in patients with type 2 diabetes who have a high risk of macrovascular events.
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| 11. |
- Lauria, A., et al.
(författare)
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BMI is an important driver of beta-cell loss in type 1 diabetes upon diagnosis in 10 to 18-year-old children
- 2015
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Ingår i: European Journal of Endocrinology. - : BioScientifica. - 0804-4643 .- 1479-683X. ; 172:2, s. 107-113
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Body weight-related insulin resistance probably plays a role in progression to type 1 diabetes, but has an uncertain impact following diagnosis. In this study, we investigated whether BMI measured at diagnosis was an independent predictor of C-peptide decline 1-year post-diagnosis. Design: Multicentre longitudinal study carried out at diagnosis and up to 1-year follow-up. Methods: Data on C-peptide were collected from seven diabetes centres in Europe. Patients were grouped according to age at diagnosis (less than5 years, n = 126; greater than5 years less than10 years, n = 295; greater than10 years less than18 years, n = 421; greater than18 years, n = 410). Linear regression was used to investigate whether BMI was an independent predictor of change in fasting C-peptide over 1 year. Models were additionally adjusted for baseline insulin dose and HbA1c. Results: In individuals diagnosed between 0 and 5 years, 5 and 10 years and those diagnosed greater than18 years, we found no association between BMI and C-peptide decline. In patients aged 10-18 years, higher BMI at baseline was associated with a greater decline in fasting C-peptide over 1 year with a decrease (beta 95% CI; P value) of 0.025 (0.010, 0.041) nM/kg per m(2) higher baseline BMI (P = 0.001). This association remained significant after adjusting for gender and differences in HbA1c and insulin dose (beta = 0.026, 95% CI = 0.0097, 0.042; P = 0.002). Conclusions: These observations indicate that increased body weight and increased insulin demand are associated with more rapid disease progression after diagnosis of type 1 diabetes in an age group 10-18 years. This should be considered in studies of beta-cell function in type 1 diabetes.
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| 12. |
- Scherbaum, W. A., et al.
(författare)
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Efficacy and tolerability of vildagliptin in drug-naive patients with type 2 diabetes and mild hyperglycaemia
- 2008
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Ingår i: Diabetes, Obesity and Metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 10:8, s. 675-682
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Tidskriftsartikel (refereegranskat)abstract
- Aim: This study was conducted to assess efficacy and tolerability of vildagliptin in drug-naive patients with type 2 diabetes and mild hyperglycaemia. Methods: Multicentre, double-blind, randomized, placebo-controlled, parallel-group study of 52-week treatment with vildagliptin (50 mg q.d.) in 306 drug-naive patients with type 2 diabetes (A1C = 6.2-7.5%). A1C, fasting plasma glucose (FPG) and measures of prandial glucose control and beta-cell function determined during standard meal tests were assessed. Results: Baseline A1C and FPG averaged 6.7% and 7.1 mmol/l, respectively, in patients randomized to vildagliptin (n = 156) and 6.8% and 7.2 mmol/l in those randomized to placebo (n = 150). A1C decreased modestly in vildagliptin-treated patients (Delta = -0.2 +/- 0.1%) and increased in patients receiving placebo (Delta = 0.1 +/- 0.1%). The between-group difference (vildagliptin - placebo) in adjusted mean change (AM Delta) in A1C was -0.3 +/- 0.1% (p < 0.001). FPG increased in patients receiving placebo (Delta = 0.5 +/- 0.1 mmol/l) and to a significantly lesser extent in vildagliptin-treated patients (between-group difference in AM Delta FPG = -0.4 +/- 0.2 mmol/l, p = 0.032). Relative to placebo, 2-h postprandial glucose (PPG) decreased (-0.9 +/- 0.4 mmol/l, p = 0.012), and insulin secretory rate (ISR) relative to glucose [ISR area under the curve (AUC)(0-2) (h)/glucose AUC(0-2) (h)] increased (+5.0 +/- 1.2 pmol/min/m(2)/mM, p < 0.001). Mean body weight decreased by 0.5 +/- 0.3 kg in vildagliptin-treated patients and by 0.2 +/- 0.3 kg in patients receiving placebo. The side-effect profile of vildagliptin was similar to that of placebo, and one hypoglycaemic episode occurred in one patient receiving placebo. Conclusions: In drug-naive patients with mild hyperglycaemia, relative to placebo, 52-week treatment with vildagliptin 50 mg q.d. significantly decreases A1C, FPG and PPG and improves beta-cell function without weight gain or hypoglycaemia.
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| 13. |
- Scherbaum, W. A., et al.
(författare)
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Evidence that vildagliptin attenuates deterioration of glycaemic control during 2-year treatment of patients with type 2 diabetes and mild hyperglycaemia
- 2008
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Ingår i: Diabetes, Obesity and Metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 10:11, s. 1114-1124
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To assess the 2-year efficacy and tolerability of vildagliptin (50 mg once daily) in patients with type 2 diabetes (T2DM) and mild hyperglycaemia. Methods: This was a multicentre, randomized, double-blind, placebo-controlled trial comprising a 52-week core study with a 4-week, active treatment-free washout followed by a 52-week extension study with another washout period conducted in 131 drug-naive patients with T2DM and mild hyperglycaemia [glycosylated haemoglobin ( HbA(1c)) 6.2-7.2%]. All patients received lifestyle counselling at each study visit. Efficacy and tolerability were assessed during visits at weeks 0 (core study baseline), 4, 8, 12, 16, 24, 32, 40 and 52 of active treatment; at week 56 (i.e. after the first washout period); at weeks 68, 80, 96 and 108 and at week 112 (i.e. after the second washout period). Standard meal tests were also performed at weeks 0, 24, 52, 56, 80, 108 and 112 to assess postprandial glycaemia and beta-cell function, which was quantified by glucose area under the curve (AUC(0-2) (h))/insulin secretory rate (ISR) AUC(0-2) (h) (ISR/G). Changes from baseline and between-treatment differences (placebo-adjusted changes from baseline during vildagliptin treatment) were analysed by ANCOVA. Results: The placebo-adjusted change from week 0 in HbA(1c) was -0.3 +/- 0.1% after 1 year of vildagliptin treatment (p < 0.001) and -0.5 +/- 0.2% after 2 years (p = 0.008). The placebo-adjusted change from core study baseline in fasting plasma glucose, in glucose AUC(0-2) (h) and in the beta-cell function parameter, ISR/G, tended to be greater after 2 years than after 1 year of treatment with vildagliptin. Even after a 4-week washout, the placebo-adjusted change from week 0 to week 112 in ISR/G was 3.2 +/- 1.6 pmol/min/m(2)/mM (p = 0.058) and the placebo-adjusted difference in the change from week 0 to week 112 in HbA(1c) was -0.3 +/- 0.1% (p = 0.051). The incidences of adverse events (AEs), serious AEs and discontinuations because of AEs were similar in the two treatment groups, and hypoglycaemic episodes were reported by no patient receiving vildagliptin and by two patients receiving placebo. Conclusions: In drug-naive patients with mild hyperglycaemia, 2-year treatment with vildagliptin 50 mg once daily attenuated the progressive loss of glycaemic control seen in patients receiving only lifestyle counselling ( and placebo). This appears to be because of a corresponding attenuation of the deterioration of beta-cell function as assessed by ISR/G.
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