Moore Allan F, Jablonski Kathleen A, Mason Clinton C, McAteer Jarred B, Arakaki Richard F, Goldstein Barry J, Kahn Steven E, Kitabchi Abbas E, Hanson Robert L, Knowler William C, Florez Jose C
Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114-2622, USA.
J Clin Endocrinol Metab. 2009 Feb;94(2):449-55. doi: 10.1210/jc.2008-1583. Epub 2008 Nov 18.
Insulin resistance is an important feature of type 2 diabetes. Ectoenzyme nucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) inhibits insulin signaling, and a recent meta-analysis reported a nominal association between the Q allele in the K121Q (rs1044498) single nucleotide polymorphism in its gene ENPP1 and type 2 diabetes. OBJECTIVE AND INTERVENTION: We examined the impact of this polymorphism on diabetes incidence as well as insulin secretion and sensitivity at baseline and after treatment with a lifestyle intervention or metformin vs. placebo in the Diabetes Prevention Program (DPP). DESIGN, SETTING, PARTICIPANTS, AND OUTCOME: We genotyped ENPP1 K121Q in 3548 DPP participants and performed Cox regression analyses using genotype, intervention, and interactions as predictors of diabetes incidence.
Fasting glucose and glycated hemoglobin were higher in QQ homozygotes at baseline (P < 0.001 for both). There was a significant interaction between genotype at rs1044498 and intervention under the dominant model (P = 0.03). In analyses stratified by treatment arm, a positive association with diabetes incidence was found in Q allele carriers compared to KK homozygotes [hazard ratio (HR), 1.38; 95% confidence interval (CI), 1.08-1.76; P = 0.009] in the placebo arm (n = 996). Lifestyle modification eliminated this increased risk. These findings persisted after adjustment for body mass index and race/ethnicity. Association of ENPP1 K121Q genotype with diabetes incidence under the additive and recessive genetic models showed consistent trends [HR, 1.10 (95% CI, 0.99-1.23), P = 0.08; and HR, 1.16 (95% CI, 0.92-1.45), P = 0.20, respectively] but did not reach statistical significance.
ENPP1 K121Q is associated with increased diabetes incidence; the DPP lifestyle intervention eliminates this increased risk.
胰岛素抵抗是2型糖尿病的一个重要特征。胞外酶核苷酸焦磷酸酶磷酸二酯酶1（ENPP1）抑制胰岛素信号传导，最近一项荟萃分析报道，其基因ENPP1中K121Q（rs1044498）单核苷酸多态性的Q等位基因与2型糖尿病之间存在名义上的关联。目的与干预措施：我们在糖尿病预防计划（DPP）中，研究了这种多态性对糖尿病发病率以及基线时和生活方式干预或二甲双胍与安慰剂治疗后胰岛素分泌和敏感性的影响。设计、地点、参与者及结果：我们对3548名DPP参与者的ENPP1 K121Q进行了基因分型，并使用基因型、干预措施及相互作用作为糖尿病发病率的预测因素进行了Cox回归分析。
基线时，QQ纯合子的空腹血糖和糖化血红蛋白较高（两者P均<0.001）。在显性模型下，rs1044498的基因型与干预措施之间存在显著的相互作用（P = 0.03）。在按治疗组分层的分析中，在安慰剂组（n = 996）中，与KK纯合子相比，Q等位基因携带者与糖尿病发病率呈正相关[风险比（HR），1.38；95%置信区间（CI），1.08 - 1.76；P = 0.009]。生活方式改变消除了这种增加的风险。在调整体重指数和种族/民族后，这些发现仍然存在。在加性和隐性遗传模型下，ENPP1 K121Q基因型与糖尿病发病率的关联显示出一致的趋势[HR分别为1.10（95%CI，0.99 - 1.23），P = 0.08；以及HR为1.16（95%CI，0.92 - 1.45），P = 0.20]，但未达到统计学显著性。
ENPP1 K121Q与糖尿病发病率增加有关；DPP生活方式干预消除了这种增加的风险。
