Abu-Toamih Atamni Hanifa J, Ziner Yaron, Mott Richard, Wolf Lior, Iraqi Fuad A
Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv, 69978, Tel Aviv, Israel.
The Blavatnik School of Computer Science, Tel-Aviv University, Tel Aviv, Israel.
Mamm Genome. 2017 Feb;28(1-2):20-30. doi: 10.1007/s00335-016-9667-2. Epub 2016 Nov 2.
Type-2 diabetes (T2D) is a complex metabolic disease characterized by impaired glucose tolerance. Despite environmental high risk factors, host genetic background is a strong component of T2D development. Herein, novel highly genetically diverse strains of collaborative cross (CC) lines from mice were assessed to map quantitative trait loci (QTL) associated with variations of glucose-tolerance response. In total, 501 mice of 58 CC lines were maintained on high-fat (42 % fat) diet for 12 weeks. Thereafter, an intraperitoneal glucose tolerance test (IPGTT) was performed for 180 min. Subsequently, the values of Area under curve for the glucose at zero and 180 min (AUC), were measured, and used for QTL mapping. Heritability and coefficient of variations in glucose tolerance (CVg) were calculated. One-way analysis of variation was significant (P < 0.001) for AUC between the CC lines as well between both sexes. Despite Significant variations for both sexes, QTL analysis was significant, only for females, reporting a significant female-sex-dependent QTL (~2.5 Mbp) associated with IPGTT AUC trait, located on Chromosome 8 (32-34.5 Mbp, containing 51 genes). Gene browse revealed QTL for body weight/size, genes involved in immune system, and two main protein-coding genes involved in the Glucose homeostasis, Mboat4 and Leprotl1. Heritability and coefficient of genetic variance (CVg) were 0.49 and 0.31 for females, while for males, these values 0.34 and 0.22, respectively. Our findings demonstrate the roles of genetic factors controlling glucose tolerance, which significantly differ between sexes requiring independent studies for females and males toward T2D prevention and therapy.
2型糖尿病（T2D）是一种以葡萄糖耐量受损为特征的复杂代谢性疾病。尽管存在环境高风险因素，但宿主遗传背景是T2D发病的重要组成部分。在此，对来自小鼠的新型高度遗传多样的协作杂交（CC）品系进行评估，以定位与葡萄糖耐量反应变异相关的数量性状位点（QTL）。总共58个CC品系的501只小鼠在高脂（42%脂肪）饮食下饲养12周。此后，进行180分钟的腹腔葡萄糖耐量试验（IPGTT）。随后，测量葡萄糖在0和180分钟时的曲线下面积（AUC）值，并用于QTL定位。计算葡萄糖耐量的遗传力和变异系数（CVg）。CC品系之间以及两性之间，AUC的单向方差分析均具有显著性（P<0.0（此处原文有误，推测应为P<0.001））。尽管两性均存在显著差异，但QTL分析仅对雌性具有显著性，报告了一个与IPGTT AUC性状相关的显著的雌性性别依赖性QTL（约2.5 Mbp），位于8号染色体（32 - 34.5 Mbp，包含51个基因）上。基因浏览揭示了体重/体型的QTL、参与免疫系统的基因以及参与葡萄糖稳态的两个主要蛋白质编码基因Mboat4和Leprotl1。雌性的遗传力和遗传方差系数（CVg）分别为0.49和0.31，而雄性的这些值分别为0.34和0.22。我们的研究结果证明了控制葡萄糖耐量的遗传因素的作用，两性之间存在显著差异，因此在T2D的预防和治疗方面，需要对雌性和雄性进行独立研究。
