Replication of association of ENPP1 polymorphisms and haplotypes with severe obesity in a Greek study population

Abstract The ENPP1 (Ectonucleotide pyrophosphatase/phosphodiesterase 1) gene, encoding a protein that negatively modulates insulin receptor activation, remains relatively understudied in obesity genetics. Moreover, the evidence of association of single nucleotide polymorphisms (SNPs), K12Q, IVS20delT-11 and A/G+1044TGA, and of the risk haplotype Q–delT–G with obesity risk is uncertain and is mostly driven by studies in Central-Northern European populations. This study aimed to examine the replication of association of adult severe obesity with the above-mentioned SNPs and with the risk haplotype Q–delT–G, in a Greek study population. We studied 979 Greek individuals (mean age ~ 48years old), which included 510 adults with severe obesity (BMI≥35Kg/m 2 ) and 469 normal-weight (BMI<25Kg/m 2 ) controls. Three ENPP1 SNPs (rs1044498, rs1799774 and rs7754561) were genotyped using the TaqMan allelic discrimination assay. Logistic regression was applied to detect association of SNPs with obesity. Linkage disequilibrium among the three SNPs was assessed, and haplotype frequencies were compared between groups. The three SNPs did not exhibit any association with severe obesity. The three SNPs were in partial linkage disequilibrium (r 2  ≤ 0.43). ENPP1 haplotype distribution differed significantly between normal-weight individuals and those with severe obesity (likelihood ratio x 2  = 13.38, P = 0.020), with the Q–delT–G haplotype found to be present exclusively in individuals with severe obesity (frequency 3.3%) and to be associated with severe obesity (x 2  = 5.66, P = 0.017; reference haplotype KTA). Our study was able to replicate the association of the Q–delT–G haplotype with increased susceptibility to severe obesity in a Greek adult population.