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

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dc.contributor.author Stolerman, Elliot S. en_US
dc.contributor.author Manning, Alisa K. en_US
dc.contributor.author McAteer, Jarred B. en_US
dc.contributor.author Dupuis, Josée en_US
dc.contributor.author Fox, Caroline S. en_US
dc.contributor.author Cupples, L. Adrienne en_US
dc.contributor.author Meigs, James B. en_US
dc.contributor.author Florez, Jose C. en_US
dc.date.accessioned 2011-12-29T22:21:54Z
dc.date.available 2011-12-29T22:21:54Z
dc.date.issued 2011-12-29
dc.identifier.citation Stolerman, Elliot S., Alisa K. Manning, Jarred B. McAteer, Josée Dupuis, Caroline S. Fox, L. Adrienne Cupples, James B. Meigs, Jose C. Florez. "Haplotype Structure of the ENPP1 Gene and Nominal Association of the K121Q Missense Single Nucleotide Polymorphism With Glycemic Traits in the Framingham Heart Study" Diabetes 57(7): 1971-1977. (2008) en_US
dc.identifier.issn 1939-327X en_US
dc.identifier.uri http://hdl.handle.net/2144/2573
dc.description.abstract OBJECTIVE: A recent meta-analysis demonstrated a nominal association of the ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) K→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 ≥5%) with an r2 value ≥0.80. 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 = 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 = 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. en_US
dc.description.sponsorship National Institutes of Health Training Grant (T32 GM007748); American Diabetes Association Career Development Award; National Institute of Diabetes and Digestive and Kidney Diseases Grant (K24-DK-080140); GlaxoSmithKline; Sanofi-aventis; National Institutes of Health Research Career Award (K23-DK-65978-04); National Heart, Lung, and Blood Institute’s Framingham Heart Study (N01-HC-25195); National Institutes of Health National Center for Research Resources Shared Instrumentation Grant (1S10-RR-163736-01A1) en_US
dc.language.iso en en_US
dc.publisher American Diabetes Association en_US
dc.rights Copyright 2008, American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit,and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. en_US
dc.title Haplotype Structure of the ENPP1 Gene and Nominal Association of the K121Q Missense Single Nucleotide Polymorphism With Glycemic Traits in the Framingham Heart Study en_US
dc.type article en_US
dc.identifier.doi 10.2337/db08-0266 en_US
dc.identifier.pubmedid 18426862 en_US
dc.identifier.pmcid 2453609 en_US

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