Replication Study of ENPP1 Variants and Haplotypes Associated with Severe Obesity in a Greek Adult Population

The ENPP1 (Ectonucleotide pyrophosphatase/phosphodiesterase 1) gene, encoding a protein that negatively modulates insulin receptor activation, remains relatively understudied in obesity genetics. K121Q (rs1044498; chr6:132,172,368: A > C) and other ENPP1 genetic variants (rs1799774; chr6:132,203,471: insT> delT and rs7754561; chr6:132,212,694: A > G), as well as the risk haplotype Q-delT-G have been investigated for their association with obesity risk mostly in populations from Central and Northern Europe, yielding controversial findings. Given the significance of reproducibility in genetic association studies and the scarcity of data from Southern Europe, we performed a case-control replication study to test the hypothesis that ENPP1 variants and haplotypes are associated with severe obesity in the underexplored and high-risk Greek population. A total of 979 Greek individuals (mean age: 47.6 ± 12.5years old), including 510 adults with severe obesity (BMI≥35Kg/m²) and 469 normal-weight (18.5 < BMI<25Kg/m²) controls, were studied. Three ENPP1 variants (rs1044498, rs1799774 and rs7754561) were genotyped using the TaqMan allelic discrimination assay. Logistic regression was applied to detect association of variants with obesity. Linkage disequilibrium among the three variants was assessed, and haplotype frequencies were compared between groups. The three variants did not exhibit any association with adult severe obesity. The three variants were in partial linkage disequilibrium (r² ≤ 0.43). ENPP1 haplotype distribution differed significantly between normal-weight individuals and those with adult severe obesity (likelihood ratio x² = 13.38, P = 0.020), with the Q-delT-G haplotype found to be present exclusively in individuals with adult severe obesity (frequency 3.3%) and to be associated with adult severe obesity (x² = 5.66, P = 0.017; reference haplotype K-InsT-A, consisting of the three major alleles of the three variants). Our replication findings contribute novel evidence regarding the genetic architecture of adult severe obesity in a Southern-European population, however larger studies are necessary to validate these results.