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Integrative Biology

Contribution of 24 obesity-associated genetic variants to insulin resistance, pancreatic beta-cell function and type 2 diabetes risk in the French population

International Journal of Obesity volume 37, pages 980–985 (2013)Cite this article

Subjects

Abstract

Context:

Obesity is the major determinant of type 2 diabetes (T2D), presumably through its effect on insulin resistance. Genome-wide association studies reported many single-nucleotide polymorphisms (SNPs) that increase obesity risk and body mass index (BMI), but their impact on T2D-related traits and risk is unclear.

Objective:

We aimed at analyzing the effect of 24 obesity risk alleles, separately and in combination, on variation of both insulin resistance and β-cell dysfunction, and on T2D risk.

Design:

We genotyped 24 obesity-associated SNPs and calculated an obesity genotype score (sum of the obesity risk alleles per individual). We analyzed the contribution of each SNP and this score to the variation of four metabolic indices: homeostasis model assessment of insulin resistance (HOMA-IR), homeostasis model assessment of the pancreatic β-cell function (HOMA-B), insulin sensitivity index (ISI) and insulinogenic index (II) (in up to 8050 nondiabetic French individuals) and to T2D risk (in 2077 T2D cases and 3085 controls).

Results:

We found a highly significant effect of the obesity genotype score on increased insulin resistance adjusted for age and gender (β=0.02; P-value=7.16 × 10−9 for HOMA-IR). Individually, we identified nominal or significant association between increased insulin resistance and risk alleles in FAIM2, FTO, GNPDA2, MC4R, NPC1, PTER and SH2B1. Most signals, including the obesity genotype score and FTO SNP, were also associated with increased β-cell function (β=0.01; P-value=1.05 × 10−6 and β=0.04; P-value=3.45 × 10−4, respectively). In our T2D case–control study, only the obesity genotype score and the well-known FTO locus significantly contributed to T2D risk (OR=1.03; P-value=9.99 × 10−3 and OR=1.15; P-value=9.46 × 10−4, respectively). Adjustment for BMI abolished all significant associations.

Conclusions:

Genetic predisposition to obesity contributes to increased insulin resistance and to its compensation through increased β-cell function, and weakly increases the T2D risk. These associations are mediated by BMI.

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Acknowledgements

We are sincerely indebted to all participants of the genetic study. Data on glycaemic traits have been contributed by MAGIC investigators and have been downloaded from www.magicinvestigators.org. Our study was supported by the EU-funded EurOCHIP FP7 consortium and the French ‘Agence Nationale de la Recherche’. DM is funded by a Tier 2 Canada Research Chair.

Author information

Author notes

  1. S Robiou-du-Pont and A Bonnefond: These authors contributed equally to this work.

Authors and Affiliations

  1. CNRS UMR-8199, Lille Pasteur Institute, Lille, France

    S Robiou-du-Pont, L Yengo, E Vaillant, S Lobbens, E Durand & P Froguel

  2. Ecole Doctorale de Biologie-Santé, Lille Nord de France University, Lille, France

    S Robiou-du-Pont, L Yengo, E Vaillant, S Lobbens, E Durand & P Froguel

  3. Inserm-U695, Université Paris VII−Paris Diderot, Faculté de Médecine Xavier Bichat, Paris, France

    A Bonnefond & M Marre

  4. Paediatric Endocrine Department, Lille Teaching Hospital, Lille, France

    J Weill

  5. Institut inter-régional pour la santé (IRSA), La Riche, France

    O Lantieri

  6. Inserm-U780, Centre for Research in Epidemiology and Population Health, Villejuif, France

    B Balkau

  7. Santé publique, Paris-Sud 11 University, Orsay, France

    B Balkau

  8. Department of Endocrinology and Diabetology, Corbeil-Essonnes Hospital, Essonnes, France

    G Charpentier

  9. Department of Endocrinology, Diabetology and Nutrition, Bichat-Claude Bernard University Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France

    M Marre

  10. Department of Genomic Medicine, Hammersmith Hospital, Imperial College London, London, UK

    P Froguel

  11. Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontaro, Canada

    D Meyre

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  1. S Robiou-du-Pont
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Correspondence to A Bonnefond or D Meyre.

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Robiou-du-Pont, S., Bonnefond, A., Yengo, L. et al. Contribution of 24 obesity-associated genetic variants to insulin resistance, pancreatic beta-cell function and type 2 diabetes risk in the French population. Int J Obes 37, 980–985 (2013). https://doi.org/10.1038/ijo.2012.175

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