| 21. |
- Moore, Allan F, et al.
(författare)
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Extension of type 2 diabetes genome-wide association scan results in the diabetes prevention program
- 2008
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Ingår i: Diabetes. - Alexandria : American diabetes association. - 0012-1797 .- 1939-327X. ; 57:9, s. 2503-2510
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Genome-wide association scans (GWASs) have identified novel diabetes-associated genes. We evaluated how these variants impact diabetes incidence, quantitative glycemic traits, and response to preventive interventions in 3,548 subjects at high risk of type 2 diabetes enrolled in the Diabetes Prevention Program (DPP), which examined the effects of lifestyle intervention, metformin, and troglitazone versus placebo.RESEARCH DESIGN AND METHODS: We genotyped selected single nucleotide polymorphisms (SNPs) in or near diabetes-associated loci, including EXT2, CDKAL1, CDKN2A/B, IGF2BP2, HHEX, LOC387761, and SLC30A8 in DPP participants and performed Cox regression analyses using genotype, intervention, and their interactions as predictors of diabetes incidence. We evaluated their effect on insulin resistance and secretion at 1 year.RESULTS: None of the selected SNPs were associated with increased diabetes incidence in this population. After adjustments for ethnicity, baseline insulin secretion was lower in subjects with the risk genotype at HHEX rs1111875 (P = 0.01); there were no significant differences in baseline insulin sensitivity. Both at baseline and at 1 year, subjects with the risk genotype at LOC387761 had paradoxically increased insulin secretion; adjustment for self-reported ethnicity abolished these differences. In ethnicity-adjusted analyses, we noted a nominal differential improvement in beta-cell function for carriers of the protective genotype at CDKN2A/B after 1 year of troglitazone treatment (P = 0.01) and possibly lifestyle modification (P = 0.05).CONCLUSIONS: We were unable to replicate the GWAS findings regarding diabetes risk in the DPP. We did observe genotype associations with differences in baseline insulin secretion at the HHEX locus and a possible pharmacogenetic interaction at CDKNA2/B.
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| 22. |
- Pan, Qing, et al.
(författare)
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Variation at the Melanocortin 4 Receptor Gene and Response to Weight-Loss Interventions in the Diabetes Prevention Program
- 2013
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Ingår i: Obesity. - : Wiley-Blackwell. - 1930-7381 .- 1930-739X. ; 21:9, s. E520-E526
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To assess associations and genotype x treatment interactions for melanocortin 4 receptor (MC4R) locus variants and obesity-related traits.Design and Methods: Diabetes prevention program (DPP) participants (N = 3,819, of whom 3,356 were genotyped for baseline and 3,234 for longitudinal analyses) were randomized into intensive lifestyle modification (diet, exercise, weight loss), metformin or placebo control. Adiposity was assessed in a subgroup (n = 909) using computed tomography. All analyses were adjusted for age, sex, ethnicity and treatment.Results: The rs1943218 minor allele was nominally associated with short-term (6 month; P = 0.032) and long-term (2 year; P = 0.038) weight change. Eight SNPs modified response to treatment on short-term (rs17066856, rs9966412, rs17066859, rs8091237, rs17066866, rs7240064) or long-term (rs12970134, rs17066866) reduction in body weight, or diabetes incidence (rs17066829) (all P-interaction < 0.05).Conclusion: This is the first study to comprehensively assess the role of MC4R variants and weight regulation in a weight loss intervention trial. One MC4R variant was directly associated with obesity-related traits or diabetes; numerous other variants appear to influence body weight and diabetes risk by modifying the protective effects of the DPP interventions.
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| 23. |
- Papandonatos, George D, et al.
(författare)
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Genetic Predisposition to Weight Loss and Regain With Lifestyle Intervention : Analyses From the Diabetes Prevention Program and the Look AHEAD Randomized Controlled Trials
- 2015
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 64:12, s. 4312-4321
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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.
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| 24. |
- Pollin, Toni I., et al.
(författare)
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Genetic Modulation of Lipid Profiles following Lifestyle Modification or Metformin Treatment: The Diabetes Prevention Program
- 2012
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 8:8
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Tidskriftsartikel (refereegranskat)abstract
- Weight-loss interventions generally improve lipid profiles and reduce cardiovascular disease risk, but effects are variable and may depend on genetic factors. We performed a genetic association analysis of data from 2,993 participants in the Diabetes Prevention Program to test the hypotheses that a genetic risk score (GRS) based on deleterious alleles at 32 lipid-associated single-nucleotide polymorphisms modifies the effects of lifestyle and/or metformin interventions on lipid levels and nuclear magnetic resonance (NMR) lipoprotein subfraction size and number. Twenty-three loci previously associated with fasting LDL-C, HDL-C, or triglycerides replicated (P = 0.04-1x10(-17)). Except for total HDL particles (r = -0.03, P = 0.26), all components of the lipid profile correlated with the GRS (partial |r| = 0.07-0.17, P=5x10(-5)-1x10(-19)). The GRS was associated with higher baseline-adjusted 1-year LDL cholesterol levels (beta = +0.87, SEE +/- 0.22 mg/dl/allele, P=8x10(-5), P-interaction = 0.02) in the lifestyle intervention group, but not in the placebo (beta = +0.20, SEE +/- 0.22 mg/dl/allele, P = 0.35) or metformin (beta = -0.03, SEE +/- 0.22 mg/dl/allele, P = 0.90; P-interaction = 0.64) groups. Similarly, a higher GRS predicted a greater number of baseline-adjusted small LDL particles at 1 year in the lifestyle intervention arm (beta = +0.30, SEE +/- 0.012 ln nmol/L/allele, P = 0.01, P-interaction = 0.01) but not in the placebo (beta = 20.002, SEE +/- 0.008 ln nmol/L/allele, P = 0.74) or metformin (beta = +0.013, SEE +/- 0.008 nmol/L/allele, P = 0.12; P-interaction = 0.24) groups. Our findings suggest that a high genetic burden confers an adverse lipid profile and predicts attenuated response in LDL-C levels and small LDL particle number to dietary and physical activity interventions aimed at weight loss.
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| 25. |
- Varga, Tibor V., et al.
(författare)
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Comprehensive Analysis of Established Dyslipidemia-Associated Loci in the Diabetes Prevention Program
- 2016
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Ingår i: Circulation. - : Lippincott Williams & Wilkins. - 1942-325X .- 1942-3268. ; 9:6, s. 495-503
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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.
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