Genetic Predisposition to Long-Term Nondiabetic Deteriorations in Glucose Homeostasis: Ten-Year Follow-Up of the GLACIER Study

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Genetic Predisposition to Long-Term Nondiabetic Deteriorations in Glucose Homeostasis: Ten-Year Follow-Up of the GLACIER Study

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Title: Genetic Predisposition to Long-Term Nondiabetic Deteriorations in Glucose Homeostasis: Ten-Year Follow-Up of the GLACIER Study
Author: Renström, Frida; Shungin, Dmitry; Johansson, Ingegerd; Hallmans, Göran; Franks, Paul W.; Florez, Jose Carlos; Hu, Frank B.

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Citation: Renström, Frida, Dmitry Shungin, Ingegerd Johansson, Jose C. Florez, Göran Hallmans, Frank B. Hu, and Paul W. Franks. 2011. Genetic predisposition to long-term nondiabetic deteriorations in glucose homeostasis: Ten-year follow-up of the GLACIER study. Diabetes 60(1): 345-354.
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Abstract: Objective: To assess whether recently discovered genetic loci associated with hyperglycemia also predict long-term changes in glycemic traits. Research Design and Methods: Sixteen fasting glucose-raising loci were genotyped in middle-aged adults from the Gene x Lifestyle interactions And Complex traits Involved in Elevated disease Risk (GLACIER) Study, a population-based prospective cohort study from northern Sweden. Genotypes were tested for association with baseline fasting and 2-h postchallenge glycemia (N = 16,330), and for changes in these glycemic traits during a 10-year follow-up period (N = 4,059). Results: Cross-sectional directionally consistent replication with fasting glucose concentrations was achieved for 12 of 16 variants; 10 variants were also associated with impaired fasting glucose (IFG) and 7 were independently associated with 2-h postchallenge glucose concentrations. In prospective analyses, the effect alleles at four loci (GCK rs4607517, ADRA2A rs10885122, DGKB-TMEM195 rs2191349, and G6PC2 rs560887) were nominally associated with worsening fasting glucose concentrations during 10-years of follow-up. MTNR1B rs10830963, which was predictive of elevated fasting glucose concentrations in cross-sectional analyses, was associated with a protective effect on postchallenge glucose concentrations during follow-up; however, this was only when baseline fasting and 2-h glucoses were adjusted for. An additive effect of multiple risk alleles on glycemic traits was observed: a weighted genetic risk score (80th vs. 20th centiles) was associated with a 0.16 mmol/l (P = 2.4 × 10\(^{−6}\)) greater elevation in fasting glucose and a 64% (95% CI: 33–201%) higher risk of developing IFG during 10 years of follow-up. Conclusions: Our findings imply that genetic profiling might facilitate the early detection of persons who are genetically susceptible to deteriorating glucose control; studies of incident type 2 diabetes and discrete cardiovascular end points will help establish whether the magnitude of these changes is clinically relevant.
Published Version: doi:10.2337/db10-0933
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3012192/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:10303244
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