Dashti Mohammed, Ali Naser M, Alsaleh Hussain, John Sumi Elsa, Nizam Rasheeba, Thanaraj Thangavel Alphonse, Al-Mulla Fahd
Genetics and Bioinformatics Department, Dasman Diabetes Institute, Kuwait City, Kuwait.
Department of Medical Laboratories, Ahmadi Hospital, Kuwait Oil Company (KOC), Ahmadi, Kuwait.
Front Endocrinol (Lausanne). 2024 Nov 26;15:1443737. doi: 10.3389/fendo.2024.1443737. eCollection 2024.
Numerous studies have linked mitochondrial dysfunction to the development of type 2 diabetes (T2D) by affecting glucose-stimulated insulin secretion in pancreatic beta cells and reducing oxidative phosphorylation in insulin-responsive tissues. Given the strong genetic underpinnings of T2D, research has explored the connection between mitochondrial DNA haplogroups, specific variants, and the risk and comorbidities of T2D. For example, haplogroups F, D, M9, and N9a have been linked to an elevated risk of T2D across various populations. Additionally, specific mitochondrial DNA variants, such as the rare mtDNA 3243 A>G and the more prevalent mtDNA 16189 T>C, have also been implicated in heightened T2D risk. Notably, these associations vary among different populations. Given the high incidence of T2D in the Gulf Cooperation Council countries, this study investigates the correlation between T2D and mitochondrial haplogroups and variants in Arab populations from the Gulf region.
This analysis involved mitochondrial haplogroup and variant testing in a cohort of 1,112 native Kuwaiti and Qatari individuals, comprising 685 T2D patients and 427 controls. Complete mitochondrial genomes were derived from whole exome sequencing data to examine the associations between T2D and haplogroups and mitochondrial DNA variants.
The analysis revealed a significant protective effect of haplogroup H against T2D (odds ratio [OR] = 0.65; P = 0.022). This protective association persisted when adjusted for age, sex, body mass index (BMI) and population group, with an OR of 0.607 (P = 0.021). Furthermore, specific mitochondrial variants showed significant associations with T2D risk after adjustment for relevant covariates, and some variants were exclusively found in T2D patients.
Our findings confirm that the maternal haplogroup H, previously identified as protective against obesity in Kuwaiti Arabs, also serves as a protective factor against T2D in Arabs from the Gulf region. The study also identifies mitochondrial DNA variants that either increase or decrease the risk of T2D, underscoring their role in cellular energy metabolism.
众多研究已将线粒体功能障碍与2型糖尿病（T2D）的发生联系起来，其通过影响胰腺β细胞中葡萄糖刺激的胰岛素分泌以及降低胰岛素反应性组织中的氧化磷酸化来实现。鉴于T2D有强大的遗传基础，研究已探索线粒体DNA单倍群、特定变异与T2D风险及合并症之间的联系。例如，单倍群F、D、M9和N9a在不同人群中均与T2D风险升高有关。此外，特定的线粒体DNA变异，如罕见的线粒体DNA 3243 A>G和更常见的线粒体DNA 16189 T>C，也与T2D风险增加有关。值得注意的是，这些关联在不同人群中有所不同。鉴于海湾合作委员会国家T2D的高发病率，本研究调查了海湾地区阿拉伯人群中T2D与线粒体单倍群及变异之间的相关性。
该分析对1112名科威特和卡塔尔本地人进行了线粒体单倍群和变异检测，其中包括685名T2D患者和427名对照。完整的线粒体基因组来自全外显子测序数据，以检查T2D与单倍群及线粒体DNA变异之间的关联。
分析显示单倍群H对T2D有显著的保护作用（优势比[OR]=0.65；P=0.022）。在对年龄、性别、体重指数（BMI）和人群组进行调整后，这种保护关联仍然存在，OR为0.607（P=0.021）。此外，在对相关协变量进行调整后，特定的线粒体变异与T2D风险显示出显著关联，并且一些变异仅在T2D患者中发现。
我们的研究结果证实，先前被确定为对科威特阿拉伯人肥胖有保护作用的母系单倍群H，在海湾地区的阿拉伯人中也是预防T2D的保护因素。该研究还确定了增加或降低T2D风险的线粒体DNA变异，强调了它们在细胞能量代谢中的作用。
