The K121Q polymorphism in
ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is associated with
type 2 diabetes and
obesity. The possibility of other ENPP1 polymorphisms influencing these phenotypes has received little attention. Our aim was to examine the associations of tagging single nucleotide polymorphisms (SNPs) and haplotypes of the linkage disequilibrium (LD) block containing K121Q polymorphism with
type 2 diabetes in a Polish population, controlling for any effect of
obesity. We genotyped 426 type 2 diabetic case and 370 control subjects for seven SNPs in ENPP1. In the total group, neither
type 2 diabetes nor
obesity was significantly associated with any SNP. However, in obese subjects, two SNPs were significantly associated with
type 2 diabetes: the Q allele of K121Q (odds ratio 1.6 [95% CI 1.003-2.6]) and T allele of rs997509 (4.7 [1.6-13.9]). In the LD block, four SNPs plus the K121Q polymorphism distinguished six haplotypes, three of which carried the Q allele. Interestingly, the T allele of rs997509 sufficed to distinguish a 121Q-carrying haplotype that was significantly more associated with
type 2 diabetes than the other two (4.2 [1.3-13.5]). These other two 121Q-carrying haplotypes were not associated with
type 2 diabetes. In conclusion, we found a new SNP, rs997509, in intron 1 that is strongly associated with risk of
type 2 diabetes in obese individuals. The molecular mechanisms underlying this association are unknown.