Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, 4200 Fifth Avenue, Pittsburgh, PA 15260, USA.
Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, EH16 4UX, Scotland, United Kingdom of Great Britain and Northern Ireland.
J Diabetes Complications. 2021 Apr;35(4):107842. doi: 10.1016/j.jdiacomp.2020.107842. Epub 2021 Jan 9.
To examine candidate insulin resistance single nucleotide polymorphisms (SNPs) for associations with glycemic control, insulin resistance, BMI, and complications in an observational type 1 diabetes (T1D) cohort: the Pittsburgh Epidemiology of Diabetes Complications (EDC) study.
In 422 European-ancestry participants, we assessed associations using additive models between 15 candidate SNPs and 25-year mortality, cardiovascular disease, microalbuminuria, overt nephropathy and proliferative retinopathy, and 25-year mean HbA1c, estimated glucose disposal rate (eGDR, inverse measure of insulin resistance), and BMI.
The A allele of rs12970134 was associated with higher mean HbA1c (β = +0.34 ± 0.09, p = 0.00009) and nominally associated with worse eGDR (p = 0.02). Further analyses suggest the HbA1c association may be modified by diabetes therapy regimen: rs12970134 AA genotype was associated with higher HbA1c under non-intensive therapy conditions (<3 insulin injections/day or monitoring blood glucose<3 times/day [p = 0.004]), but not under intensive therapy (≥3 injections/day or insulin pump and monitoring glucose≥3 times/day [p = 0.71]). There were no significant associations between any SNPs and BMI or complications.
rs12970134, near MC4R, is strongly associated with HbA1c in this cohort. Further exploration of this genomic region is warranted, as it may hold promise for discovering new therapeutic targets to improve glycemic control in T1D.
在观察性 1 型糖尿病（T1D）队列中，即匹兹堡糖尿病并发症流行病学（EDC）研究，研究候选胰岛素抵抗单核苷酸多态性（SNP）与血糖控制、胰岛素抵抗、体重指数和并发症的相关性。
在 422 名欧洲血统参与者中，我们使用加性模型评估了 15 个候选 SNP 与 25 年死亡率、心血管疾病、微量白蛋白尿、显性肾病和增殖性视网膜病变以及 25 年平均 HbA1c、估计葡萄糖处置率（eGDR，胰岛素抵抗的逆测指标）和 BMI 之间的关联。
rs12970134 的 A 等位基因与平均 HbA1c 升高相关（β=+0.34±0.09，p=0.00009），并与 eGDR 降低有显著关联（p=0.02）。进一步的分析表明，HbA1c 关联可能受糖尿病治疗方案的修饰：rs12970134 AA 基因型与非强化治疗条件下（每天少于 3 次胰岛素注射或监测血糖<3 次/天 [p=0.004]）的 HbA1c 升高相关，但在强化治疗条件下（每天注射≥3 次或胰岛素泵和监测血糖≥3 次/天 [p=0.71]）不相关。任何 SNP 与 BMI 或并发症之间均无显著关联。
在该队列中，MC4R 附近的 rs12970134 与 HbA1c 强烈相关。需要进一步探索该基因组区域，因为它可能为发现改善 T1D 血糖控制的新治疗靶点提供希望。
