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

Abstract

OBJECTIVE-A recent meta-analysis demonstrated a nominal association of the ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) K3 Q missense single nucleotide polymorphism (SNP) at position 121 with type 2 diabetes. We set out to confirm the association of ENPP1 K121Q with hyperglycemia, expand this association to insulin resistance traits, and determine whether the association stems from K121Q or another variant in linkage disequilibrium with it.RESEARCH DESIGN AND METHODS-We characterized the haplotype structure of ENPP1 and selected 39 tag SNPs that captured 96% of common variation in the region (minor allele frequency Ն5%) with an r 2 value Ն0.80. We genotyped the SNPs in 2,511 Framingham Heart Study participants and used age-and sex-adjusted linear mixed effects (LME) models to test for association with quantitative metabolic traits. We also examined whether interaction between K121Q and BMI affected glycemic trait levels. RESULTS-The Q allele of K121Q (rs1044498) was associated with increased fasting plasma glucose (FPG), A1C, fasting insulin, and insulin resistance by homeostasis model assessment (HOMA-IR; all P ϭ 0.01-0.006). Two noncoding SNPs (rs7775386 and rs7773477) demonstrated similar associations, but LME models indicated that their effects were not independent from K121Q. We found no association of K121Q with obesity, but interaction models suggested that the effect of the Q allele on FPG and HOMA-IR was stronger in those with a higher BMI (P ϭ 0.008 and 0.01 for interaction, respectively).CONCLUSIONS-The Q allele of ENPP1 K121Q is associated with hyperglycemia and insulin resistance in whites. We found an adiposity-SNP interaction, with a stronger association of K121Q with diabetes-related quantitative traits in people with a higher BMI. 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 (2-7). 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). It has also been reported that insulin receptor autophosphorylation in fibroblasts is decreased in Q allele carriers compared with KK homozygotes (2). Thus, the ENPP1 gene is considered to be a likely candidate gene for insulin resistance and type 2 diabetes (9).Multiple studies have shown both positive and negative evidence of association between variants in ENPP1 and obesity, type 2 diabetes, and related traits. Most recently, Meyre et al. (5) found that a haplotype formed by three SNPs ...

Morphological and biochemical features of obesity are associated with mineralization genes’ polymorphisms

“…10,11,49,50 The question of ENPP1's functional importance in OB etiology is complicated by negative results obtained in other association studies. 12,51 The distribution of association signals across the ENPP1 gene locus observed in this study (see Figure 1b) suggests that associations with OB traits (for example BMI and leptin) may be driven by the 3 0 UTR region, and not necessarily by K121Q polymorphism. This hypothesis is supported by several earlier studies that reported associations of OB-related traits with markers in ENPP1 3 0 UTR.…”

Genetic Associations with Metabolic Syndrome and Its Quantitative Traits by Race/Ethnicity in the United States

“…Even though large consortia meta-analyses have not reported variants near ENPP1, we included it in our analysis because of strong prior associations of rs1044498 with IR. [27][28][29] The C allele at rs1260326 near GCKR is associated with higher IR and lower TG levels 30 ; we therefore used the T alleles at this locus as the risk alleles in analyses of TG levels. Two of the seven SNPs associated with IR are also associated with increased BMI (rs9939609 near FTO and rs11152213 near MCR4).…”

The association of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) K121Q gene polymorphism with the risk of type 2 diabetes mellitus in European, American, and African populations: a meta-analysis

“…ENPP1 is a transmembrane glycoprotein that inhibits the tyrosine kinase activity of IR and down-regulates insulin signaling in cells (11) through inhibiting the autophosphorylation of IR and impairing insulin signaling downstream of IR (12). A study found that the 121Q variant has a greater inhibitory action on IR than does the 121K variant (13).…”

“…ENPP1 is a transmembrane glycoprotein that down-regulates insulin signaling in cells by inhibiting the tyrosine kinase activity of the insulin receptor (11). The measurement results of this variable were each allele in ENPP1 K121Q gene including dominant (K), recessive (Q), dominant homozygous (KK), recessive homozygous (QQ), and heterozygous (KQ).…”

“…The enzyme is highly expressed in adipocytes and is also found in other tissues involved in glucose and lipid metabolism, including liver, skeletal muscle, and β-cells of the pancreas (10). ENPP1 is a transmembrane glycoprotein that down-regulates insulin signaling in cells by inhibiting the tyrosine kinase activity of the insulin receptor (IR), perhaps by interaction with its α-subunit (11). The ENPP1 is a promising candidate gene for T2DM because it inhibits autophosphorylation of IR and impairs insulin signaling downstream of IR (12).…”