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Variants of ENPP1 are associated with childhood and adult obesity and increase the risk of glucose intolerance and type 2 diabetes

Nature Genetics volume 37, pages 863–867 (2005)Cite this article

Abstract

We identified a locus on chromosome 6q16.3–q24.2 (ref. 1) associated with childhood obesity that includes 2.4 Mb common to eight genome scans for type 2 diabetes (T2D) or obesity1,2,3,4,5,6,7,8. Analysis of the gene ENPP1 (also called PC-1), a candidate for insulin resistance9,10, in 6,147 subjects showed association between a three-allele risk haplotype (K121Q, IVS20delT–11 and A→G+1044TGA; QdelTG) and childhood obesity (odds ratio (OR) = 1.69, P = 0.0006), morbid or moderate obesity in adults (OR = 1.50, P = 0.006 or OR = 1.37, P = 0.02, respectively) and T2D (OR = 1.56, P = 0.00002). The Genotype IBD Sharing Test suggested that this obesity-associated ENPP1 risk haplotype contributes to the observed chromosome 6q linkage with childhood obesity. The haplotype confers a higher risk of glucose intolerance and T2D to obese children and their parents and associates with increased serum levels of soluble ENPP1 protein in children. Expression of a long ENPP1 mRNA isoform, which includes the obesity-associated A→G+1044TGA SNP, was specific for pancreatic islet beta cells, adipocytes and liver. These findings suggest that several variants of ENPP1 have a primary role in mediating insulin resistance and in the development of both obesity and T2D, suggesting that an underlying molecular mechanism is common to both conditions.

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Figure 1: Pairwise LD between 53 SNPs in a 580-kb region including ENPP1 in 421 obese children and 298 control individuals.
Figure 2: Allelic association of 53 SNPs in the 580-kb region including ARG1, CRSP3, ENPP3, ENPP1 and CTGF.
Figure 3

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Acknowledgements

We thank the affected individuals and their families who participated in this study; T. Woodage and Applied Biosystems for technical support; S. Gaget, S. Lobbens, E. Durand, S. Lahmidi, S. Poulain, M. Deweirder, F. Allegaert, V. Delannoy-Vasseur and C. Letierce for technical assistance; and M. Tauber for giving access to the Toulouse obese children DNA Bank. This work was supported in part by Conseil Regional Nord-Pas de Calais/FEDER ARCir and “Association Française des Diabétiques” funding and by AFERO/Roche and ALFEDIAM/Roche Diagnostics research prizes. I.D.G. and B.A.M. were supported by a grant from the US National Institutes of Health.

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Authors and Affiliations

  1. CNRS 8090-Institute of Biology, Pasteur Institute, Lille, France

    David Meyre, Nabila Bouatia-Naji, Chantal Samson, Cécile Lecoeur, Vincent Vatin, Maya Ghoussaini, Christophe Wachter, Philippe Boutin, Christian Dina & Philippe Froguel

  2. Section of Genomic Medicine and Genome Centre, Hammersmith Campus, Du Cane Road, Imperial College London, London, W12 0NN, UK

    David Meyre, Cécile Lecoeur, Andrew Walley & Philippe Froguel

  3. EA3502, Hôtel-Dieu Hospital, Paris, France

    Agnès Tounian & Karine Clément

  4. INSERM U557/INRA U1125, ISTNA, Paris, France

    Serge Hercberg

  5. Endocrinology-Diabetology Unit, Corbeil-Essonnes Hospital, France

    Guillaume Charpentier

  6. Paracelsus Private Medical School, Salzburg, Austria

    Wolfgang Patsch

  7. INSERM ERIT-M 0106, University of Lille 2, Lille, France

    François Pattou

  8. INSERM, U258-IFR69, Paris Sud Faculty of Medicine, Villejuif, France

    Marie-Aline Charles

  9. Department of Pediatric Gastroenterology and Nutrition, Trousseau Hospital, Paris, France

    Patrick Tounian

  10. INSERM U563, Children's Hospital, Toulouse, France

    Béatrice Jouret

  11. Pediatric Endocrine Unit, Jeanne de Flandre Hospital, Lille, France

    Jacques Weill

  12. Department of Medicine and Diabetes Center, University of California San Francisco, San Francisco, California, USA

    Betty A Maddux & Ira D Goldfine

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  1. David Meyre
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Corresponding author

Correspondence to Philippe Froguel.

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Supplementary information

Supplementary Fig. 1

Correlation of the ENPP1 protein serum level with Z score of BMI in 279 children. (PDF 217 kb)

Supplementary Fig. 2

mRNA expression of PC-1/ENPP1 in human tissues. (PDF 217 kb)

Supplementary Table 1

Phenotypic characteristics of “6q-evidence” families. (PDF 62 kb)

Supplementary Table 2

Polymorphisms in 5′ and 3′ proximal regions, exons and boundaries of ENPP1 gene. (PDF 47 kb)

Supplementary Table 3

Association (p<0.05) of genotypes and alleles of ENPP1 gene SNPs with obesity. (PDF 68 kb)

Supplementary Table 4

Description of the French and Austrian samples used in the study. (PDF 48 kb)

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Meyre, D., Bouatia-Naji, N., Tounian, A. et al. Variants of ENPP1 are associated with childhood and adult obesity and increase the risk of glucose intolerance and type 2 diabetes. Nat Genet 37, 863–867 (2005). https://doi.org/10.1038/ng1604

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