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

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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Correspondence to Philippe Froguel.

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The authors declare no competing financial interests.

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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