Mitochondrial DNA variants, copy number and haplogroups in type 2 diabetes: A systematic review and meta-analysis in different ethnic population

Type 2 diabetes mellitus (T2DM) exhibits noticeable ethnic disparities in prevalence, pathophysiology, and treatment response. Nuclear genome-wide association studies explain only a fraction of T2DM heritability. Mitochondrial DNA (mtDNA) variants, copy number alterations, and haplogroups have been implicated in disease susceptibility, but prior evidence has been inconsistent and population-specific. We systematically searched seven databases (PubMed, Embase, Web of Science, Google Scholar, ScienceDirect, Scopus, CNKI) from 1998 to 2025, following PRISMA 2020 guidelines. Qualified studies included investigations of mtDNA variants, copy number, and haplogroups in relation to T2DM. Two authors independently screened, extracted data, and assessed quality using the Newcastle-Ottawa Scale and the Q-Genie tool specific to genetic association studies. Sensitivity analyses were conducted restricting to studies meeting key genetic quality criteria: Hardy-Weinberg equilibrium testing, population stratification control, and multiple testing corrections. Random-effects meta-analyses and subgroup analyses were conducted. From a systematic review of 48 studies (comprising of 28,178 participants), we identified 30 studies (24,467 participants) suitable for quantitative meta-analysis. Higher mtDNA copy number has been found to play protective role against developing T2D i.e., risk of T2DM increases by 32 % with each unit decrease in mtDNA-copy number [OR = 0.68 (95 % CI: 0.52–0.89, p = 0.005] with moderate heterogeneity (I 2 = 64 %). This association was consistent across European, Asian, and American populations. Variant A3243G represented the most pathogenic variant across all populations (OR = 3.45). We also identified associations of novel D-loop variant T16189C had stronger effects in Asian populations (OR = 1.31, p = 0.001). Haplogroup N9a was protective in East Asians (OR = 0.71) conferring 29 % protection. Mechanistic observation highlighted impaired oxidative phosphorylation, elevated reactive oxygen species, and inflammatory activation. This seven-database meta-analysis provides the most definitive evidence to date for mtDNA contributions to T2DM, demonstrating universal copy number effects and ancestry-dependent variant associations. Findings support the integration of mtDNA biomarkers into risk prediction, ancestry-informed clinical algorithms, and pharmacogenomic strategies, offering a pathway toward precision medicine in diabetes prevention and management. • Lower mtDNA copy number is consistently associated with increased T2DM risk across populations • Pathogenic mtDNA variant A3243G shows a strong, universal association with T2DM • mtDNA variant T16189C and haplogroup N9a exhibit clear ethnicity-specific effects • Findings support mtDNA-based biomarkers for ancestry-informed diabetes risk prediction