New Polymorphism of ENPP1 (PC-1) Is Associated With Increased Risk of Type 2 Diabetes Among Obese Individuals

Abstract

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. Diabetes 55: 2626 -2630, 2006 T he ectonucleotide pyrophosphatase/phosphodiesterase 1 gene (ENPP1 or PC-1) is located on the long arm of chromosome 6 (6q23.2) and encodes for a protein that inhibits insulin signaling (1). A polymorphism in exon 4 (K121Q) of the gene has been examined for association with features of insulin resistance, type 2 diabetes, and obesity with inconsistent results. The 121Q allele was associated with insulin resistance in nondiabetic subjects in many (2-8) but not in all (2,3,9,10) populations. Similarly, it was associated with type 2 diabetes in South Asians living in India and in the U.S., as well as in Caucasians living in the U.S. (2,3) and Finland (6) but not Caucasians in Sweden (4) or Denmark (10). Although a recent study (11) found no association of obesity with the 121Q allele, Meyre et al. (12) recently reported that a particular haplotype, defined by 121Q and alleles at two other single nucleotide polymorphisms (SNPs) (a T deletion at IVS20 delT-11 and G allele at A3 Gϩ1044TGA/rs7754561), was associated with obesity as well as increased risk of type 2 diabetes. However, the role of obesity is unclear from this study. Does the 121Q allele increase the risk of type 2 diabetes directly or through its effect on obesity?Several factors may explain the discrepant effects of the 121Q allele on metabolic traits in different populations. Its effect may be modified by environmental factors or functional polymorphisms in other genes (13), either of which may vary across populations. Unknown polymorphisms within ENPP1 that influence these meta...

The ENPP1 K121Q Polymorphism Is Associated With Type 2 Diabetes in European Populations

“…Indeed, recently a meta-analysis and a meta-regression have shown that the deleterious effect of the PPARG P12/P12 genotype on diabetes risk is augmented in studies where control subjects were leaner (25), thus suggesting that this may be a common phenomenon characterizing the effect of insulin resistance genes on the risk of type 2 diabetes. Since our meta-regression of ENPP1 K121Q is limited by the use of population BMI averages rather than individual measures, we cannot verify whether our present finding is related to the reported interaction between the K121Q polymorphism and BMI in modulating the risk of type 2 diabetes (15,21,22).…”

Haplotype Structure of the ENPP1 Gene and Nominal Association of the K121Q Missense Single Nucleotide Polymorphism With Glycemic Traits in the Framingham Heart Study

“…Having established the association between ENPP1 K121Q and hyperglycemia, we explored the interaction between K121Q and BMI because of preliminary evidence that the effect of the Q allele on glycemic traits is mediated by an increase in adiposity (3,5,7,13,30) and suggestions that this variant may also contribute to obesity traits (5,6,(31)(32)(33). Although we observed no association of ENPP1 K121Q with BMI or waist circumference, our interaction analysis supports the observation that a higher BMI strengthens the association of this particular polymorphism with elevated insulin resistance and glucose levels.…”

“…Diabetes 57: [1971][1972][1973][1974][1975][1976][1977]2008 E ctonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1), also known as plasma cell membrane glycoprotein 1 (PC-1), is a transmembrane glycoprotein that down-regulates insulin signaling in cells by inhibiting the tyrosine kinase activity of the insulin receptor, perhaps by interaction with its ␣-subunit (1). Within the coding region of ENPP1, a K3 Q missense single nucleotide polymorphism (SNP) at position 121 (K121Q; rs1044498) has been previously associated with insulin resistance and related abnormalities in some studies (2)(3)(4)(5)(6)(7). The molecular mechanism thought to be responsible for the role of the Q121 variant is a "gain of function" of the ENPP1 protein inhibitory activity on the insulin receptor (8).…”

Clinical Application of 1,5-Anhydroglucitol Measurements in Patients with Hepatocyte Nuclear Factor-1α Maturity-Onset Diabetes of the Young

“…The first group, 47 apparently healthy control subjects who were normoglycemic in the fasting condition, contained spouses of patients with MODY and volunteers from the medical personnel of the Department of Metabolic Diseases. The second group included 43 patients with type 2 diabetes diagnosed at age Ն35 years for whom no insulin therapy was used for at least 2 years after diagnosis, ascertained as previously described (13). The same exclusion criteria were used as for the MODY group.…”