Santoro Nicola, Chen Ling, Todd Jennifer, Divers Jasmin, Shah Amy S, Gidding Samuel S, Burke Brian, Haymond Morey, Lange Leslie, Marcovina Santica, Flannick Jason, Caprio Sonia, Florez Jose C, Srinivasan Shylaja
Division of Pediatric Endocrinology, Yale School of Medicine, New Haven, CT, USA.
Department of Medicine and Health Sciences "V. Tiberio," University of Molise, Campobasso, Italy.
J Endocr Soc. 2021 Aug 18;5(11):bvab139. doi: 10.1210/jendso/bvab139. eCollection 2021 Nov 1.
Dyslipidemia is highly prevalent in youth with type 2 diabetes (T2D), yet the pathogenic components of dyslipidemia in youth with T2D are poorly understood.
To evaluate the genetic determinants of lipid traits in youth with T2D through a genome-wide association study.
We genotyped 206 928 variants and imputed 17 642 824 variants in 1076 youth (mean age 15.0 ± 2.48 years) with T2D from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) and SEARCH for Diabetes in Youth (SEARCH) studies as part of the Progress in Diabetes Genetics in Youth (ProDiGY) consortium. We performed association testing for triglyceride and low-density lipoprotein cholesterol and high-density lipoprotein cholesterol (HDL-c) concentrations adjusted for the genetic relationship matrix within each substudy followed by meta-analyses for each trait.
We identified a novel association between a deletion on chromosome 3 (3:67817380_AT/A_Deletion:RP11-81N13.1) and triglyceride levels at genome-wide level of significance ( = 2.3 × 10) with each risk allele increasing triglycerides by 20%. We also identified a genome-wide significant signal at rs247617 ( = 5.1 × 10) between and associated with HDL-c, with carriers of 1 copy of the risk allele having twice higher HDL-c.
Our genetic analyses of lipid traits in youth with T2D have identified 1 novel and 1 previously known locus. Additional studies are needed to further characterize the genetic architecture of dyslipidemia in youth with T2D.
血脂异常在2型糖尿病（T2D）青年患者中极为普遍，但对T2D青年患者血脂异常的致病成分了解甚少。
通过全基因组关联研究评估T2D青年患者脂质特征的遗传决定因素。
设计、参与者和主要结局指标：作为青年糖尿病遗传学进展（ProDiGY）联盟的一部分，我们对来自青少年和青年2型糖尿病治疗选择（TODAY）研究以及青年糖尿病SEARCH（SEARCH）研究的1076例T2D青年患者（平均年龄15.0±2.48岁）的206928个变异进行基因分型，并推算出17642824个变异。我们对甘油三酯、低密度脂蛋白胆固醇和高密度脂蛋白胆固醇（HDL-c）浓度进行关联测试，并在每个亚研究中根据遗传关系矩阵进行调整，随后对每个特征进行荟萃分析。
我们在3号染色体上的一个缺失（3:67817380_AT/A_Deletion:RP11-81N13.1）与全基因组水平显著的甘油三酯水平之间发现了一种新的关联（=2.3×10），每个风险等位基因使甘油三酯增加20%。我们还在rs247617（=5.1×10）处发现了一个全基因组显著信号，与HDL-c相关，携带1个拷贝风险等位基因的个体HDL-c水平高出两倍。
我们对T2D青年患者脂质特征的遗传分析确定了1个新位点和1个先前已知的位点。需要进一步的研究来进一步表征T2D青年患者血脂异常的遗传结构。
