Chirita-Emandi Adela, Munteanu Diana, Andreescu Nicoleta, Tutac Paul, Paul Corina, Velea Iulian Puiu, Pusztai Agneta Maria, Hlistun Victoria, Boiciuc Chiril, Sacara Victoria, Vudu Lorina, Usurelu Natalia, Puiu Maria
Center of Genomic Medicine, University of Medicine and Pharmacy "Victor Babes", Timisoara, Romania.
"Louis Turcanu" Emergency Hospital for Children, Timisoara, Romania.
J Pediatr Endocrinol Metab. 2019 Jan 28;32(1):33-39. doi: 10.1515/jpem-2018-0288.
Background Previous genome-wide association studies (GWAS) identified IGF1, IRS1, GCKR, PPARG, GCK1 and KCTD1 as candidate genes for insulin resistance and type 2 diabetes (T2D). We investigated the associations of these previously reported common variants in these genes with insulin resistance in overweight children from Romania and Moldova. Methods Six single nucleotide polymorphisms (SNPs), IGF1 (rs35767), IRS1 (rs2943634), GCKR (rs780094), PPARG (rs1801282), GCK1 (rs1799884) and KCTD15 (rs29941), were genotyped in 100 overweight children along with clinical and metabolic parameters. Homeostatic model assessment of insulin resistance (HOMA-IR) above 3.4 (defining insulin resistance) was used as the outcome. Results Children differed in insulin resistance status despite having similar body mass index (BMI) standard deviation scores (SDS) (World Health Organization, [WHO] reference). The identified predictors for altered insulin metabolism were higher cholesterol levels, higher diastolic blood pressure and higher waist-to-hip-ratio (as a marker for increased abdominal fat). None of the SNPs showed significant association with increase in the risk for insulin resistance in children (p range=0.478-0.724; odds ratio [OR] range=1.924-4.842); however, the risk allele in GCKR (rs780094, p=0.06, OR=6.871) demonstrated near statistical significance. Conclusions The interrogated risk alleles did not show any significant association with insulin resistance in children in our cohort; however, the GCKR (rs780094) might be a viable candidate in larger cohorts. The lack of replication of the proposed association may point to differences in linkage disequilibrium or effect modifiers across studies.
背景 先前的全基因组关联研究（GWAS）确定IGF1、IRS1、GCKR、PPARG、GCK1和KCTD15为胰岛素抵抗和2型糖尿病（T2D）的候选基因。我们调查了这些基因中先前报道的常见变异与罗马尼亚和摩尔多瓦超重儿童胰岛素抵抗之间的关联。方法 对100名超重儿童进行了6个单核苷酸多态性（SNP）的基因分型，包括IGF1（rs35767）、IRS1（rs2943634）、GCKR（rs780094）、PPARG（rs1801282）、GCK1（rs1799884）和KCTD15（rs29941），同时测量了临床和代谢参数。以胰岛素抵抗稳态模型评估（HOMA-IR）大于3.4（定义为胰岛素抵抗）作为结局。结果 尽管儿童的体重指数（BMI）标准差评分（SDS）相似（世界卫生组织[WHO]参考标准），但他们的胰岛素抵抗状态存在差异。已确定的胰岛素代谢改变的预测因素是较高的胆固醇水平、较高的舒张压和较高的腰臀比（作为腹部脂肪增加的标志物）。没有一个SNP与儿童胰岛素抵抗风险增加显著相关（p值范围=0.478 - 0.724；比值比[OR]范围=1.924 - 4.842）；然而，GCKR中的风险等位基因（rs780094，p = 0.06，OR = 6.871）显示出接近统计学意义。结论 在我们的队列中，所检测的风险等位基因与儿童胰岛素抵抗没有任何显著关联；然而，GCKR（rs780094）在更大的队列中可能是一个可行的候选基因。所提出的关联缺乏重复性可能表明不同研究之间连锁不平衡或效应修饰存在差异。
