Haplotype structure of the ENPP1 Gene and Nominal Association of the K121Q missense single nucleotide polymorphism with glycemic traits in the Framingham Heart Study.
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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作者：
Stolerman ES;Manning AK;McAteer JB;Dupuis J;Fox CS;Cupples LA;Meigs JB;Florez JC
最近的一项荟萃分析表明，外核苷酸焦磷酸酶磷酸二酯酶1（ENPP 1）121位K→Q错义单核苷酸多态性（SNP）与2型糖尿病存在名义关联。我们着手确认ENPP 1 K121 Q与高血糖症的关联，将这种关联扩展到胰岛素抵抗性状，研究设计和方法-我们描述了ENPP 1的单倍型结构，并选择了39个标签SNP，这些SNP捕获了该区域96%的常见变异（次要等位基因频率≥5%），r2值≥0.80。我们对2，511名心脏病研究参与者的SNP进行了基因分型，并使用年龄和性别调整的线性混合效应（LME）模型来测试与定量代谢特征的相关性。我们还研究了K121 Q和BMI之间的相互作用是否影响血糖性状水平。经稳态模型评估，K121 Q（rs 1044498）的Q等位基因与空腹血糖（FPG）、A1 C、空腹胰岛素和胰岛素抵抗升高相关（HOMA-IR;所有P = 0.01-0.006）。两个非编码SNPs（rs7775386和rs7773477）表现出类似的关联，但LME模型表明，它们的影响并不独立于K121 Q。我们没有发现K121 Q与肥胖相关，但交互作用模型表明，Q等位基因对FPG和HOMA-IR的影响在BMI较高的人群中更强（交互作用分别为P = 0.008和0.01）。结论：ENPP 1 K121 Q的Q等位基因与白人的高血糖和胰岛素抵抗相关。我们发现了一种肥胖-SNP相互作用，在BMI较高的人群中，K121 Q与糖尿病相关的数量性状有更强的关联。
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.
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