Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Kuwait, Kuwait.
Department of Pharmacology and Toxicology, Faculty of Medicine, Kuwait University, Kuwait, Kuwait.
Front Endocrinol (Lausanne). 2023 Oct 4;14:1185956. doi: 10.3389/fendo.2023.1185956. eCollection 2023.
The Wolfram syndrome 1 gene ( is the main causative locus for Wolfram syndrome, an inherited condition characterized by childhood-onset diabetes mellitus, optic atrophy, and deafness. Global genome-wide association studies have listed at least 19 variants that are associated with type 2 diabetes (T2D) and metabolic traits. It has been suggested that miRNA binding sites on play a critical role in the regulation of the wolframin protein, and loss of WFS1 function may lead to the pathogenesis of diabetes. In the Hungarian population, it was observed that a 3' UTR variant from , namely rs1046322, influenced the affinity of miR-668 to mRNA, and showed a strong association with T2D. In this study, we genotyped a large cohort of 2067 individuals of different ethnicities residing in Kuwait for the rs1046322 polymorphism. The cohort included 362 Southeast Asians (SEA), 1045 Arabs, and 660 South Asians (SA). Upon performing genetic association tests, we observed significant associations between the rs1046322 SNP and obesity traits in the SEA population, but not in the Arab or SA populations. The associated traits in SEA cohort were body mass index, BMI (β=1.562, P-value=0.0035, P), waist circumference, WC (β=3.163, P-value=0.0197, P) and triglyceride, TGL (β=0.224, P-value=0.0340). The association with BMI remained statistically significant even after multiple testing correction. Among the SEA individuals, carriers of the effect allele at the SNP had significantly higher BMI [mean of 27.63 (3.6) Kg/m], WC [mean of 89.9 (8.1) cm], and TGL levels [mean of 1.672 (0.8) mmol/l] than non-carriers of the effect allele. Our findings suggest a role for in obesity, which is a risk factor for diabetes. The study also emphasizes the significant role the ethnic background may play in determining the effect of genetic variants on susceptibility to metabolic diseases.
Wolfram 综合征 1 基因（WFS1）是 Wolfram 综合征的主要致病基因，该综合征是一种遗传性疾病，表现为儿童期发病的糖尿病、视神经萎缩和耳聋。全基因组关联研究已列出至少 19 个与 2 型糖尿病（T2D）和代谢特征相关的变异。据推测，WFS1 上的 miRNA 结合位点在调节 wolframin 蛋白方面起着关键作用，而 WFS1 功能的丧失可能导致糖尿病的发病机制。在匈牙利人群中，观察到来自 WFS1 的 3'UTR 变异体 rs1046322 影响 miR-668 与 WFS1 mRNA 的亲和力，并与 T2D 强烈相关。在这项研究中，我们对居住在科威特的不同种族的 2067 名个体进行了 rs1046322 多态性的基因分型。该队列包括 362 名东南亚人（SEA）、1045 名阿拉伯人和 660 名南亚人（SA）。进行遗传关联测试后，我们观察到 rs1046322 SNP 与 SEA 人群肥胖特征之间存在显著关联，但在阿拉伯或 SA 人群中没有。SEA 队列中相关的特征是体重指数，BMI（β=1.562，P 值=0.0035，P）、腰围，WC（β=3.163，P 值=0.0197，P）和甘油三酯，TGL（β=0.224，P 值=0.0340）。即使在经过多次测试校正后，BMI 与 SNP 的关联仍然具有统计学意义。在 SEA 个体中，携带 SNP 效应等位基因的个体 BMI[均值 27.63（3.6）kg/m]、WC[均值 89.9（8.1）cm]和 TGL 水平[均值 1.672（0.8）mmol/l]显著高于非效应等位基因携带者。我们的研究结果表明，WFS1 在外源性肥胖中起作用，而肥胖是糖尿病的一个危险因素。该研究还强调了种族背景在确定遗传变异对代谢性疾病易感性的影响方面可能发挥的重要作用。
