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Type 2 diabetes-related genetic risk scores associated with variations in fasting plasma glucose and development of impaired glucose homeostasis in the prospective DESIR study

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Abstract

Aims/hypothesis

Genome-wide association studies have firmly established 65 independent European-derived loci associated with type 2 diabetes and 36 loci contributing to variations in fasting plasma glucose (FPG). Using individual data from the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) prospective study, we evaluated the contribution of three genetic risk scores (GRS) to variations in metabolic traits, and to the incidence and prevalence of impaired fasting glycaemia (IFG) and type 2 diabetes.

Methods

Three GRS (GRS-1, 65 type 2 diabetes-associated single nucleotide polymorphisms [SNPs]; GRS-2, GRS-1 combined with 24 FPG-raising SNPs; and GRS-3, FPG-raising SNPs alone) were analysed in 4,075 DESIR study participants. GRS-mediated effects on longitudinal variations in quantitative traits were assessed in 3,927 nondiabetic individuals using multivariate linear mixed models, and on the incidence and prevalence of hyperglycaemia at 9 years using Cox and logistic regression models. The contribution of each GRS to risk prediction was evaluated using the C-statistic and net reclassification improvement (NRI) analysis.

Results

The two most inclusive GRS were significantly associated with increased FPG (β = 0.0011 mmol/l per year per risk allele, p GRS-1  = 8.2 × 10−5 and p GRS-2  = 6.0 × 10−6), increased incidence of IFG and type 2 diabetes (per allele: HR GRS-1 1.03, p = 4.3 × 10−9 and HR GRS-2 1.04, p = 1.0 × 10−16), and the 9 year prevalence (OR GRS-1 1.13 [95% CI 1.10, 1.17], p = 1.9 × 10−14 for type 2 diabetes only; OR GRS-2 1.07 [95% CI 1.05, 1.08], p = 7.8 × 10−25, for IFG and type 2 diabetes). No significant interaction was found between GRS-1 or GRS-2 and potential confounding factors. Each GRS yielded a modest, but significant, improvement in overall reclassification rates (NRI GRS-1 17.3%, p = 6.6 × 10−7; NRI GRS-2 17.6%, p = 4.2 × 10−7; NRI GRS-3 13.1%, p = 1.7 × 10−4).

Conclusions/interpretation

Polygenic scores based on combined genetic information from type 2 diabetes risk and FPG variation contribute to discriminating middle-aged individuals at risk of developing type 2 diabetes in a general population.

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Abbreviations

AROC:

Area under the receiver operating characteristic curve

DESIR:

Data from an Epidemiological Study on the Insulin Resistance Syndrome

DIAGRAM:

DIAbetes Genetics Replication And Meta-analysis

FHD:

Family history of diabetes

FPG:

Fasting plasma glucose

GRS:

Genetic risk score

GWAS:

Genome-wide association studies

HOMA2-B:

Derived HOMA index of beta cell function

HOMA2-S:

Derived HOMA index of insulin sensitivity

IFG:

Impaired fasting glycaemia

LMM:

Linear mixed model

MAGIC:

Meta-analysis of Glucose and Insulin-related traits Consortium

NFG:

Normal fasting glucose

NRI:

Net reclassification improvement

SNP:

Single nucleotide polymorphism

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Acknowledgements

We are sincerely indebted to all participants in the genetic study. We thank M. Deweirder and F. Allegaert (both at CNRS UMR 8199, Lille Pasteur Institute, Lille, France) for their invaluable management of DNA samples. The DESIR Study Group is composed of Inserm-U1018 (Paris: B. Balkau, P. Ducimetière, E. Eschwège), Inserm-U367 (Paris: F. Alhenc-Gelas), CHU d’Angers (A. Girault), Bichat Hospital (Paris: F. Fumeron, M. Marre, R. Roussel), CHU de Rennes (F. Bonnet), CNRS UMR-8199 (Lille: S. Cauchi, P. Froguel), Medical Examination Services (Alençon, Angers, Blois, Caen, Chartres, Chateauroux, Cholet, Le Mans, Orléans and Tours), Research Institute for General Medicine (J. Cogneau), the general practitioners of the region and the Cross- Regional Institute for Health (C. Born, E. Caces, M. Cailleau, N. Copin, J.G. Moreau, F. Rakotozafy, J. Tichet, S. Vol).

Funding

This study was supported by the Contrat de Projets Etat—Région Nord-Pas-DeCalais (CPER Axe Cardio-Diabète to PF), the Délégation Régionale à la Recherche et à la Technologie de la Région Nord-Pas-De-Calais, the European Union (Fonds Européen de Développement Régional to PF) and the Centre National de la Recherche Scientifique.

The DESIR study was supported by Inserm contracts with CNAMTS, Lilly, Novartis Pharma and Sanofi-aventis, and by Inserm (Réseaux en Santé Publique, Interactions entre les déterminants de la santé, Cohortes Santé TGIR 2008), the Association Diabète Risque Vasculaire, the Fédération Française de Cardiologie, La Fondation de France, ALFEDIAM, ONIVINS, Société Francophone du Diabète, Ardix Medical, Bayer Diagnostics, Becton Dickinson, Cardionics, Merck Santé, Novo Nordisk, Pierre Fabre, Roche and Topcon.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

MV and PF contributed to the conception and design of the study. MV contributed to data acquisition, analysis and interpretation, and drafted and wrote the manuscript. LY performed the data analysis, and contributed to interpretation of data and to writing the manuscript. SL and EE performed the SNP genotyping and contributed to acquisition of data. GR and AB contributed to data analysis and interpretation and to discussions. OL, MM and BB contributed to cohort study sample selection and data acquisition. PF contributed to discussions and critically revised the manuscript. All authors were involved in reviewing the manuscript and all approved the final version. MV is responsible for the integrity of the work as a whole.

Author information

Authors and Affiliations

  1. European Genomic Institute for Diabetes, FR 3508, Lille, France

    Martine Vaxillaire, Loïc Yengo, Stéphane Lobbens, Ghislain Rocheleau, Elodie Eury, Amélie Bonnefond & Philippe Froguel

  2. CNRS UMR 8199, Lille Pasteur Institute, 1 rue du Professeur Calmette, 59019, Lille Cedex, France

    Martine Vaxillaire, Loïc Yengo, Stéphane Lobbens, Ghislain Rocheleau, Elodie Eury, Amélie Bonnefond & Philippe Froguel

  3. Lille 2 University, Lille, France

    Martine Vaxillaire, Loïc Yengo, Stéphane Lobbens, Ghislain Rocheleau, Elodie Eury, Amélie Bonnefond & Philippe Froguel

  4. IRSA, La Riche, France

    Olivier Lantieri

  5. Assistance Publique–Hôpitaux de Paris, Hôpital Bichat, Diabetology Endocrinology Nutrition, Paris Diderot University, Paris, France

    Michel Marre

  6. Inserm U872, Paris, France

    Michel Marre

  7. Inserm U1018, Centre for Research in Epidemiology and Population Health, Epidemiology of Diabetes, Obesity and Chronic Renal Disease Over the Lifecourse, Villejuif, France

    Beverley Balkau

  8. Paris-Sud 11 University, UMRS 1018, Villejuif, France

    Beverley Balkau

  9. Department of Genomics of Common Disease, School of Public Health, Imperial College London, Hammersmith Hospital, Room E303, Burlington-Danes building, Du Cane Road, London, W12 0NN, UK

    Philippe Froguel

Authors
  1. Martine Vaxillaire
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  2. Loïc Yengo
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  3. Stéphane Lobbens
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  4. Ghislain Rocheleau
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  5. Elodie Eury
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  6. Olivier Lantieri
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  7. Michel Marre
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  8. Beverley Balkau
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  9. Amélie Bonnefond
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  10. Philippe Froguel
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Corresponding authors

Correspondence to Martine Vaxillaire or Philippe Froguel.

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Vaxillaire, M., Yengo, L., Lobbens, S. et al. Type 2 diabetes-related genetic risk scores associated with variations in fasting plasma glucose and development of impaired glucose homeostasis in the prospective DESIR study. Diabetologia 57, 1601–1610 (2014). https://doi.org/10.1007/s00125-014-3277-x

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