Complement C3 Associates With Incidence of Diabetes, but No Evidence of a Causal Relationship
Complement C3 Associates With Incidence of Diabetes, but No Evidence of a Causal Relationship
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DOI：
10.1210/jc.2017-00948
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发表时间：
2017-12-01
影响因子：
5.8
通讯作者：
Engstrom, Gunnar
中科院分区：
文献类型：
--
作者：
Borne, Yan;Muhammad, Iram Faqir;Engstrom, Gunnar
目的：本研究探讨血浆中补体因子3 （C3）是否与糖尿病发病率相关。我们还确定了与C3相关的遗传变异，并探讨了C3和糖尿病是否具有共同的遗传决定因素。方法：对来自马尔默饮食与癌症研究的4368名46 - 68岁非糖尿病受试者的血浆C3进行分析。在17.7 +/- 4.4年的随访期间，研究了糖尿病发病率与C3水平的关系。与C3相关的基因型是在一项全基因组关联研究中确定的。使用糖尿病遗传学复制和荟萃分析和欧洲遗传数据库进行计算机查找。结果：在18年的随访中，总共有538名（12.3%）受试者患糖尿病。经危险因素调整后，高C3与糖尿病发病率显著相关(第4四分位数vs第1四分位数的风险比为1.54（95%可信区间，1.13 ~ 2.09;P = 0.005）。C3与补体因子H位点多态性相关（P < 10(-8)）。然而，没有观察到该位点与糖尿病的关系。另有8个位点与C3相关，P < 10（-5）。其中之一，葡萄糖激酶调节蛋白（GCKR）位点，以前与糖尿病有关。C3水平与GCKR位点之间的关系在欧洲遗传数据库队列中得到了重复。结论：血浆C3浓度是糖尿病发病的危险标志。结果表明，这种关联可以部分解释为与GCKR基因相关的多效性效应。
Purpose: This study explored whether complement factor 3 (C3) in plasma is associated with incidence of diabetes in a population-based cohort. We also identified genetic variants related to C3 and explored whether C3 and diabetes share common genetic determinants.Methods: C3 was analyzed in plasma from 4368 nondiabetic subjects, 46 to 68 years old, from the Malmo Diet and Cancer Study. Incidence of diabetes was studied in relationship to C3 levels during 17.7 +/- 4.4 years of follow-up. Genotypes associated with C3 were identified in a genome-wide association study. Diabetes Genetics Replication and Meta-Analysis and the European Genetic Database were used for in silico look-up.Results: In all, 538 (12.3%) subjects developed diabetes during 18 years of follow-up. High C3 was significantly associated with incidence of diabetes after risk factor adjustments (hazard ratio comparing 4th vs 1st quartile, 1.54 (95% confidence interval, 1.13 to 2.09; P = 0.005). C3 was associated with polymorphisms at the complement factor H locus (P < 10(-8)). However, no relationship with diabetes was observed for this locus. Another eight loci were associated with C3 with P < 10(-5). One of them, the glucose kinase regulatory protein (GCKR) locus, has been previously associated with diabetes. The relationship between C3 levels and the GCKR locus was replicated in the European Genetic Database cohort.Conclusions: Plasma concentration of C3 is a risk marker for incidence of diabetes. The results suggest that this association could, in part, be explained by pleiotropic effects related to the GCKR gene.