Dataset Information

A Polygenic Lipodystrophy Genetic Risk Score Characterizes Risk Independent of BMI in the Diabetes Prevention Program.

ABSTRACT: Context:There is substantial heterogeneity in insulin sensitivity, and genetics may suggest possible mechanisms by which common variants influence this trait. Objectives:We aimed to evaluate an 11-variant polygenic lipodystrophy genetic risk score (GRS) for association with anthropometric, glycemic and metabolic traits in the Diabetes Prevention Program (DPP). In secondary analyses, we tested the association of the GRS with cardiovascular risk factors in the DPP. Design:In 2713 DPP participants, we evaluated a validated GRS of 11 common variants associated with fasting insulin-based measures of insulin sensitivity discovered through genome-wide association studies that cluster with a metabolic profile of lipodystrophy, conferring high metabolic risk despite low body mass index (BMI). Results:At baseline, a higher polygenic lipodystrophy GRS was associated with lower weight, BMI, and waist circumference measurements, but with worse insulin sensitivity index (ISI) values. Despite starting at a lower weight and BMI, a higher GRS was associated with less weight and BMI reduction at one year and less improvement in ISI after adjusting for baseline values but was not associated with diabetes incidence. A higher GRS was also associated with more atherogenic low-density lipoprotein peak-particle-density at baseline but was not associated with coronary artery calcium scores in the Diabetes Prevention Program Outcomes Study. Conclusions:In the DPP, a higher polygenic lipodystrophy GRS for insulin resistance with lower BMI was associated with diminished improvement in insulin sensitivity and potential higher cardiovascular disease risk. This GRS helps characterize insulin resistance in a cohort of individuals at high risk for diabetes, independent of adiposity.

SUBMITTER: Srinivasan S

PROVIDER: S-EPMC6694040 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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A Polygenic Lipodystrophy Genetic Risk Score Characterizes Risk Independent of BMI in the Diabetes Prevention Program.

Srinivasan Shylaja S Jablonski Kathleen A KA Knowler William C WC Dagogo-Jack Samuel S E Kahn Steven S Boyko Edward J EJ Bray George A GA Horton Edward S ES Hivert Marie-France MF Goldberg Ronald R Chen Ling L Mercader Josep J Harden Maegan M Florez Jose C JC

Journal of the Endocrine Society 20190624 9

<h4>Context</h4>There is substantial heterogeneity in insulin sensitivity, and genetics may suggest possible mechanisms by which common variants influence this trait.<h4>Objectives</h4>We aimed to evaluate an 11-variant polygenic lipodystrophy genetic risk score (GRS) for association with anthropometric, glycemic and metabolic traits in the Diabetes Prevention Program (DPP). In secondary analyses, we tested the association of the GRS with cardiovascular risk factors in the DPP.<h4>Design</h4>In ...[more]

PMID: 31428720

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Project description:BACKGROUND:Moderate alcohol consumption is associated with a decreased risk of type 2 diabetes in the general population, but little is known about the effects in individuals at high risk of diabetes. OBJECTIVES:The objectives were to determine associations between alcohol consumption and diabetes risk factors and whether alcohol consumption was a predictor of incident diabetes in individuals enrolled in the Diabetes Prevention Program (DPP). DESIGN:DPP participants (n = 3175) had impaired glucose tolerance (2-h glucose: 7.8-11.1 mmol/L), elevated fasting glucose (5.3-7.0 mmol/L), and a body mass index (in kg/m(2)) > or =24. Participants were randomly assigned to placebo, metformin, or lifestyle modification and were followed for a mean of 3.2 y. Alcohol intake was assessed at baseline and year 1 by using a semiquantitative food-frequency questionnaire. Diabetes was diagnosed by annual oral-glucose-tolerance testing and semiannual fasting plasma glucose measurement. RESULTS:Participants who reported higher alcohol consumption tended to be male, older, white, and less obese and to have a higher calorie intake and a higher HDL-cholesterol concentration. Higher alcohol consumption was associated with lower insulin secretion at any level of insulin sensitivity. We found lower incidence rates of diabetes with higher alcohol consumption in the metformin (P < 0.01 for trend) and lifestyle modification (P = 0.02 for trend) groups, which remained significant after adjustment for multiple baseline covariates. No similar association was observed in the placebo group. CONCLUSIONS:Despite overall low rates of alcohol consumption, there was a reduced risk of incident diabetes in those who reported modest daily alcohol intake and were assigned to metformin or lifestyle modification. Moderate daily alcohol intake is associated with lower insulin secretion-an effect that warrants further investigation. This trial was registered at clinicaltrials.gov as NCT00038727.

Project description:The largest and longest clinical trial of metformin for the prevention of diabetes is the Diabetes Prevention Program/Diabetes Prevention Program Outcomes Study (DPP/DPPOS). In this review, we summarise data from the DPP/DPPOS, focusing on metformin for diabetes prevention, as well as its long-term glycaemic and cardiometabolic effects and safety in people at high-risk of developing diabetes. The DPP (1996-2001) was a RCT of 3234 adults who, at baseline, were at high-risk of developing diabetes. Participants were assigned to masked placebo (n = 1082) or metformin (n = 1073) 850 mg twice daily, or intensive lifestyle intervention (n = 1079). The masked metformin/placebo intervention phase ended approximately 1 year ahead of schedule because of demonstrated efficacy. Primary outcome was reported at 2.8 years. At the end of the DPP, all participants were offered lifestyle education and 88% (n = 2776) of the surviving DPP cohort continued follow-up in the DPPOS. Participants originally assigned to metformin continued to receive metformin, unmasked. The DPP/DPPOS cohort has now been followed for over 15 years with prospective assessment of glycaemic, cardiometabolic, health economic and safety outcomes. After an average follow-up of 2.8 years, metformin reduced the incidence of diabetes by 31% compared with placebo, with a greater effect in those who were more obese, had a higher fasting glucose or a history of gestational diabetes. The DPPOS addressed the longer-term effects of metformin, showing a risk reduction of 18% over 10 and 15 years post-randomisation. Metformin treatment for diabetes prevention was estimated to be cost-saving. At 15 years, lack of progression to diabetes was associated with a 28% lower risk of microvascular complications across treatment arms, a reduction that was no different among treatment groups. Recent findings suggest metformin may reduce atherosclerosis development in men. Originally used for the treatment of type 2 diabetes, metformin, now proven to prevent or delay diabetes, may serve as an important tool in battling the growing diabetes epidemic. Long-term follow-up, currently underway in the DPP/DPPOS, is now evaluating metformin's potential role, when started early in the spectrum of dysglycaemia, on later-stage comorbidities, including cardiovascular disease and cancer.ClinicalTrials.gov NCT00038727 and NCT00004992.

Project description:BACKGROUND:The extent of weight loss among patients undergoing bariatric surgery is highly variable. Herein, we tested the contribution of genetic background to such interindividual variability after biliopancreatic diversion with duodenal switch. METHODS:Percentage of excess body weight loss (%EBWL) was monitored in 865 patients over a period of 48 months after bariatric surgery, and two polygenic risk scores were constructed with 186 and 11 (PRS186 and PRS11) single nucleotide polymorphisms previously associated with body mass index (BMI). RESULTS:The accuracy of the %EBWL logistic prediction model - including initial BMI, age, sex, and surgery modality, and assessed as the area under the receiver operating characteristics (ROC) curve adjusted for optimism (AUCadj = 0.867) - significantly increased after the inclusion of PRS186 (?AUCadj = 0.021; 95% CI of the difference [95% CIdiff] = 0.005-0.038) but not PRS11 (?AUCadj= 0.008; 95% CIdiff= -0.003-0.019). The overall fit of the longitudinal linear mixed model for %EBWL showed a significant increase after addition of PRS186 (-2 log-likelihood = 12.3; P = 0.002) and PRS11 (-2 log-likelihood = 9.9; P = 0.007). A significant interaction with postsurgery time was found for PRS186 (? = -0.003; P = 0.008) and PRS11 (? = -0.008; P = 0.03). The inclusion of PRS186 and PRS11 in the model improved the cost-effectiveness of bariatric surgery by reducing the percentage of false negatives from 20.4% to 10.9% and 10.2%, respectively. CONCLUSION:These results revealed that genetic background has a significant impact on weight loss after biliopancreatic diversion with duodenal switch. Likewise, the improvement in weight loss prediction after addition of polygenic risk scores is cost-effective, suggesting that genetic testing could potentially be used in the presurgical assessment of patients with severe obesity. FUNDING:Heart and Stroke Foundation of Canada (G-17-0016627) and Canada Research Chair in Genomics Applied to Nutrition and Metabolic Health (no. 950-231-580).

Dataset Information

A Polygenic Lipodystrophy Genetic Risk Score Characterizes Risk Independent of BMI in the Diabetes Prevention Program.

Publications

A Polygenic Lipodystrophy Genetic Risk Score Characterizes Risk Independent of BMI in the Diabetes Prevention Program.

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