Journal
NATURE GENETICS
Volume 37, Issue 8, Pages 863-867Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng1604
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Funding
- MRC [G0000477] Funding Source: UKRI
- Medical Research Council [G0000477] Funding Source: researchfish
- Medical Research Council [G0000477] Funding Source: Medline
- NIDDK NIH HHS [R01 DK056933-04S1, R01 DK056933] Funding Source: Medline
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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(1-8). Analysis of the gene ENPP1 (also called PC-1), a candidate for insulin resistance(9,10), 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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