| 1. |
- Flannick, Jason, et al.
(författare)
-
Data Descriptor : Sequence data and association statistics from 12,940 type 2 diabetes cases and controls
- 2017
-
Ingår i: Scientific Data. - : Springer Science and Business Media LLC. - 2052-4463. ; 4
-
Tidskriftsartikel (refereegranskat)abstract
- To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (> 80% of low-frequency coding variants in similar to ~82 K Europeans via the exome chip, and similar to ~90% of low-frequency non-coding variants in similar to ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.
|
|
| 2. |
- Fuchsberger, Christian, et al.
(författare)
-
The genetic architecture of type 2 diabetes
- 2016
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 536:7614, s. 41-47
-
Tidskriftsartikel (refereegranskat)abstract
- The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.
|
|
| 3. |
- Livingstone, Katherine M., et al.
(författare)
-
FTO genotype and weight loss : systematic review and meta-analysis of 9563 individual participant data from eight randomised controlled trials
- 2016
-
Ingår i: BMJ: British Medical Journal. - : BMJ. - 1756-1833. ; 354
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To assess the effect of the FTO genotype on weight loss after dietary, physical activity, or drug based interventions in randomised controlled trials.DESIGN: Systematic review and random effects meta-analysis of individual participant data from randomised controlled trials.DATA SOURCES: Ovid Medline, Scopus, Embase, and Cochrane from inception to November 2015.ELIGIBILITY CRITERIA FOR STUDY SELECTION: Randomised controlled trials in overweight or obese adults reporting reduction in body mass index, body weight, or waist circumference by FTO genotype (rs9939609 or a proxy) after dietary, physical activity, or drug based interventions. Gene by treatment interaction models were fitted to individual participant data from all studies included in this review, using allele dose coding for genetic effects and a common set of covariates. Study level interactions were combined using random effect models. Metaregression and subgroup analysis were used to assess sources of study heterogeneity.RESULTS: We identified eight eligible randomised controlled trials for the systematic review and meta-analysis (n=9563). Overall, differential changes in body mass index, body weight, and waist circumference in response to weight loss intervention were not significantly different between FTO genotypes. Sensitivity analyses indicated that differential changes in body mass index, body weight, and waist circumference by FTO genotype did not differ by intervention type, intervention length, ethnicity, sample size, sex, and baseline body mass index and age category.CONCLUSIONS: We have observed that carriage of the FTO minor allele was not associated with differential change in adiposity after weight loss interventions. These findings show that individuals carrying the minor allele respond equally well to dietary, physical activity, or drug based weight loss interventions and thus genetic predisposition to obesity associated with the FTO minor allele can be at least partly counteracted through such interventions.SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015015969.
|
|
| 4. |
- Billings, Liana K., et al.
(författare)
-
Variation in maturity-onset diabetes of the young genes influence response to interventions for diabetes prevention
- 2017
-
Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 102:8, s. 2678-2689
-
Tidskriftsartikel (refereegranskat)abstract
- Context: Variation in genes that cause maturity-onset diabetes of the young (MODY) has been associated with diabetes incidence and glycemic traits. Objectives: This study aimed to determine whether genetic variation in MODY genes leads to differential responses to insulin-sensitizing interventions. Design and Setting: This was a secondary analysis of a multicenter, randomized clinical trial, the Diabetes Prevention Program (DPP), involving 27 US academic institutions. We genotyped 22 missense and 221 common variants in the MODY-causing genes in the participants in the DPP. Participants and Interventions: The study included 2806 genotyped DPP participants randomized to receive intensive lifestyle intervention (n = 935), metformin (n = 927), or placebo (n = 944). Main Outcome Measures: Association of MODY genetic variants with diabetes incidence at a median of 3 years and measures of 1-year β-Cell function, insulinogenic index, and oral disposition index. Analyses were stratified by treatment group for significant single-nucleotide polymorphism 3 treatment interaction (Pint, 0.05). Sequence kernel association tests examined the association between an aggregate of rare missense variants and insulinogenic traits. Results: After 1 year, the minor allele of rs3212185 (HNF4A) was associated with improved β-Cell function in the metformin and lifestyle groups but not the placebo group; the minor allele of rs6719578 (NEUROD1) was associated with an increase in insulin secretion in the metformin group but not in the placebo and lifestyle groups. Conclusions: These results provide evidence that genetic variation among MODY genes may influence response to insulin-sensitizing interventions.
|
|
| 5. |
- Hivert, Marie-France, et al.
(författare)
-
Lifestyle and metformin ameliorate insulin sensitivity independently of the genetic burden of established insulin resistance variants in Diabetes Prevention Program participants.
- 2016
-
Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 65:2, s. 520-526
-
Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies of glycemic traits have identified genetics variants that are associated with insulin resistance (IR) in the general population. It is unknown if people with genetic enrichment for these IR-variants respond differently to interventions that aim to improve insulin sensitivity. We built a genetic risk score based on 17 established IR-variants and their effect sizes (weighted IR-GRS) in 2,713 participants of the Diabetes Prevention Program (DPP) with genetic consent. We tested associations between the weighted IR-GRS and insulin sensitivity index (ISI) at baseline in all participants, and with change in ISI over 1-year of follow-up in DPP intervention (metformin and lifestyle) and control (placebo) arms. All models were adjusted for age, sex, ethnicity, and waist circumference at baseline (plus baseline ISI for 1-year ISI change models). A higher IR-GRS was associated with lower baseline ISI (β= -0.754 [SE=0.229] log-ISI per unit; P=0.001 in fully adjusted models). There was no differential effect of treatment for the association between IR-GRS on change in ISI; higher IR-GRS was associated with attenuation in ISI improvement over 1 year (β= -0.520 [SE=0.233]; P=0.03 in fully adjusted models; all treatment arms). Lifestyle intervention and metformin improved ISI, regardless of the genetic burden of IR-variants.
|
|
| 6. |
- McCaffery, Jeanne M., et al.
(författare)
-
Replication of the Association of BDNF and MC4R Variants With Dietary Intake in the Diabetes Prevention Program
- 2017
-
Ingår i: Psychosomatic Medicine. - : Lippincott Williams & Wilkins. - 0033-3174 .- 1534-7796. ; 79:2, s. 224-233
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: Genomewide association studies (GWAS) have identified consistent associations with obesity, with a number of studies implicating eating behavior as a primary mechanism. Few studies have replicated genetic associations with dietary intake. This study evaluates the association between obesity susceptibility loci and dietary intake. Methods: Data were obtained as part of the Diabetes Prevention Program (DPP), a clinical trial of diabetes prevention in persons at high risk of diabetes. The association of 31 genomewide association studies identified obesity risk alleles with dietary intake, measured through a food frequency questionnaire, was investigated in 3,180 participants from DPP at baseline. Results: The minor allele at BDNF, identified as protective against obesity, was associated with lower total caloric intake (beta = -106.06, SE = 33.13; p = .0014) at experimentwide statistical significance (p = .0016), whereas association of MC4R rs571312 with higher caloric intake reached nominal significance (beta = 61.32, SE = 26.24; p = .0194). Among non-Hispanic white participants, the association of BDNF rs2030323 with total caloric intake was stronger (beta = -151.99, SE = 30.09; p < .0001), and association of FTO rs1421085 with higher caloric intake (beta = 56.72, SE = 20.69; p = .0061) and percentage fat intake (beta = 0.37, SE = 0.08; p =. 0418) was also observed. Conclusions: These results demonstrate with the strength of independent replication that BDNF rs2030323 is associated with 100 to 150 greater total caloric intake per allele, with additional contributions of MC4R and, in non-Hispanic white individuals, FTO. As it has been argued that an additional 100 kcal/d could account for the trends in weight gain, prevention focusing on genetic profiles with high dietary intake may help to quell adverse obesity trends.
|
|
| 7. |
- Papandonatos, George D, et al.
(författare)
-
Genetic Predisposition to Weight Loss and Regain With Lifestyle Intervention : Analyses From the Diabetes Prevention Program and the Look AHEAD Randomized Controlled Trials
- 2015
-
Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 64:12, s. 4312-4321
-
Tidskriftsartikel (refereegranskat)abstract
- Clinically relevant weight loss is achievable through lifestyle modification, but unintentional weight regain is common. We investigated whether recently discovered genetic variants affect weight loss and/or weight regain during behavioral intervention. Participants at high-risk of type 2 diabetes (Diabetes Prevention Program [DPP]; N = 917/907 intervention/comparison) or with type 2 diabetes (Look AHEAD [Action for Health in Diabetes]; N = 2,014/1,892 intervention/comparison) were from two parallel arm (lifestyle vs. comparison) randomized controlled trials. The associations of 91 established obesity-predisposing loci with weight loss across 4 years and with weight regain across years 2-4 after a minimum of 3% weight loss were tested. Each copy of the minor G allele of MTIF3 rs1885988 was consistently associated with greater weight loss following lifestyle intervention over 4 years across the DPP and Look AHEAD. No such effect was observed across comparison arms, leading to a nominally significant single nucleotide polymorphism x treatment interaction (P = 4.3 x 10-3). However, this effect was not significant at a study-wise significance level (Bonferroni threshold P < 5.8 x 10-4). Most obesity-predisposing gene variants were not associated with weight loss or regain within the DPP and Look AHEAD trials, directly or via interactions with lifestyle.
|
|
| 8. |
- Varga, Tibor V., et al.
(författare)
-
Comprehensive Analysis of Established Dyslipidemia-Associated Loci in the Diabetes Prevention Program
- 2016
-
Ingår i: Circulation. - : Lippincott Williams & Wilkins. - 1942-325X .- 1942-3268. ; 9:6, s. 495-503
-
Tidskriftsartikel (refereegranskat)abstract
- Background: We assessed whether 234 established dyslipidemia-associated loci modify the effects of metformin treatment and lifestyle intervention (versus placebo control) on lipid and lipid subfraction levels in the Diabetes Prevention Program randomized controlled trial. Methods and Results: We tested gene treatment interactions in relation to baseline-adjusted follow-up blood lipid concentrations (high-density lipoprotein [HDL] and low-density lipoprotein-cholesterol, total cholesterol, and triglycerides) and lipoprotein subfraction particle concentrations and size in 2993 participants with pre-diabetes. Of the previously reported single-nucleotide polymorphism associations, 32.5% replicated at P<0.05 with baseline lipid traits. Trait-specific genetic risk scores were robustly associated (3x10(-4)>P>1.1x10(-16)) with their respective baseline traits for all but 2 traits. Lifestyle modified the effect of the genetic risk score for large HDL particle numbers, such that each risk allele of the genetic risk scores was associated with lower concentrations of large HDL particles at follow-up in the lifestyle arm (beta=-0.11 mu mol/L per genetic risk scores risk allele; 95% confidence interval, -0.188 to -0.033; P=5x10(-3); P-interaction=1x10(-3) for lifestyle versus placebo), but not in the metformin or placebo arms (P>0.05). In the lifestyle arm, participants with high genetic risk had more favorable or similar trait levels at 1-year compared with participants at lower genetic risk at baseline for 17 of the 20 traits. Conclusions: Improvements in large HDL particle concentrations conferred by lifestyle may be diminished by genetic factors. Lifestyle intervention, however, was successful in offsetting unfavorable genetic loading for most lipid traits.
|
|
