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 obesity. Analysis of the gene ENPP1 (also called PC-1), a candidate for insulin resistance, 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.

Figure 1

Pairwise LD between fifty-three SNPs in a 580 kb region including the ENPP1 gene in 421 obese children and 298 control individuals. Regions of high and low LD (delta) are presented by red and blue shading, respectively. The graph is to the physical map scale.

Figure 2

Allelic association of fifty-three SNPs in the 580 kb region including the ARG1, CRSP3, ENPP3, ENPP1 and CTGF genes. Blue circles correspond to the −log₁₀ (p-value) for the comparison of allelic distribution between 421 obese children and 298 control individuals. Red circles correspond to the −log₁₀(p-value) for the comparison of allelic distribution between 62 “6q-evidence” families obese children and 298 control individuals. The figure is not to scale according to the physical map location; indeed the SNPs are equidistant to allow easy visualization of the association test results.

Figure 3

ENPP1 serum level in 89 lean children according to the presence of the risk haplotype.