Sridharan Raghavan1,2,3,4, Kathleen Jablonski5, Linda M Delahanty6,7, Nisa M Maruthur8, Aaron Leong7,9, Paul W Franks10, William C Knowler11, Jose C Florez6,7,12,13, Dana Dabelea4,14. 1. Medicine Service, Department of Veterans Affairs Eastern Colorado Healthcare System, Aurora, Colorado, USA. 2. Division of Hospital Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA. 3. Colorado Cardiovascular Outcomes Research Consortium, Aurora, Colorado, USA. 4. Centre for Lifecourse Epidemiology of Adiposity and Diabetes, Colorado School of Public Health, Aurora, Colorado, USA. 5. Department of Epidemiology and Biostatistics, Milken Institute School of Public Health, George Washington University, Washington, District of Columbia, USA. 6. Diabetes Unit and Endocrine Division, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA. 7. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. 8. Division of General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. 9. Division of General Internal Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA. 10. Department of Clinical Science, Genetic & Molecular Epidemiology Unit, Lund University Diabetes Centre, Malmö, Sweden. 11. Diabetes Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona, USA. 12. Centre for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA. 13. Programs in Metabolism and Medical & Population Genetics, Broad Institute, Cambridge, Massachusetts, USA. 14. Department of Epidemiology, Colorado School of Public Health, Aurora, Colorado, USA.
Abstract
AIM: To test whether diabetes genetic risk modifies the association of successful lifestyle changes with incident diabetes. MATERIALS AND METHODS: We studied 823 individuals randomized to the intensive lifestyle intervention (ILS) arm of the Diabetes Prevention Programme who were diabetes-free 1 year after enrolment. We tested additive and multiplicative interactions of a 67-variant diabetes genetic risk score (GRS) with achievement of three ILS goals at 1 year (≥7% weight loss, ≥150 min/wk of moderate leisure-time physical activity, and/or a goal for self-reported total fat intake) on the primary outcome of incident diabetes over 3 years of follow-up. RESULTS: A lower GRS and achieving each or all three ILS goals were each associated with lower incidence of diabetes (all P < 0.05). Additive interactions were significant between the GRS and achievement of the weight loss goal (P < 0.001), physical activity goal (P = 0.02), and all three ILS goals (P < 0.001) for diabetes risk. Achievement of all three ILS goals was associated with 1.8 (95% CI 0.3, 3.4), 3.1 (95% CI 1.5, 4.7), and 3.9 (95% CI 1.6, 6.2) fewer diabetes cases/100-person-years in the first, second and third GRS tertiles (P < 0.001 for trend). Multiplicative interactions between the GRS and ILS goal achievement were significant for the diet goal (P < 0.001), but not for weight loss (P = 0.18) or physical activity (P = 0.62) goals. CONCLUSIONS: Genetic risk may identify high-risk subgroups for whom successful lifestyle modification is associated with greater absolute reduction in the risk of incident diabetes.
AIM: To test whether diabetes genetic risk modifies the association of successful lifestyle changes with incident diabetes. MATERIALS AND METHODS: We studied 823 individuals randomized to the intensive lifestyle intervention (ILS) arm of the Diabetes Prevention Programme who were diabetes-free 1 year after enrolment. We tested additive and multiplicative interactions of a 67-variant diabetes genetic risk score (GRS) with achievement of three ILS goals at 1 year (≥7% weight loss, ≥150 min/wk of moderate leisure-time physical activity, and/or a goal for self-reported total fat intake) on the primary outcome of incident diabetes over 3 years of follow-up. RESULTS: A lower GRS and achieving each or all three ILS goals were each associated with lower incidence of diabetes (all P < 0.05). Additive interactions were significant between the GRS and achievement of the weight loss goal (P < 0.001), physical activity goal (P = 0.02), and all three ILS goals (P < 0.001) for diabetes risk. Achievement of all three ILS goals was associated with 1.8 (95% CI 0.3, 3.4), 3.1 (95% CI 1.5, 4.7), and 3.9 (95% CI 1.6, 6.2) fewer diabetes cases/100-person-years in the first, second and third GRS tertiles (P < 0.001 for trend). Multiplicative interactions between the GRS and ILS goal achievement were significant for the diet goal (P < 0.001), but not for weight loss (P = 0.18) or physical activity (P = 0.62) goals. CONCLUSIONS: Genetic risk may identify high-risk subgroups for whom successful lifestyle modification is associated with greater absolute reduction in the risk of incident diabetes.
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