Genetic drift and selective pressures shaping mitochondrial ND3 variants m.10398A>G and m.10400C>T: implications for type 2 diabetes risk in India population

Abstract

Background: Mitochondrial DNA (mtDNA) variants influence cellular energy metabolism and are implicated in metabolic diseases such as type 2 diabetes (T2D). Environmental factors, including diet and lifestyle, may shape the frequency and selection of these variants across populations. This study investigates the distribution and potential selective pressures on mtDNA variants m.10398A>G and m.10400C>T in an Indian cohort, assessing their association with T2D susceptibility.
Methods: We conducted a case-control analysis involving 206 T2D patients and 156 healthy controls to assess the frequency distribution of two significant mtDNA variants: m.10398A>G and m.10400C>T. The participants were stratified into two age groups: < 60 years and ≥ 60 years, to study the associations of age-related mitochondrial changes. The variants were genotyped using Sanger sequencing technology. We performed variant calling, multiple sequence alignment, and evolutionary conservation analysis (ConSurf). Additionally, we conducted structural impact predictions using PolyPhen-2 and protein modeling with SWISS-MODEL. For statistical analysis, we used chi-square tests along with odds ratios (OR) and 95% confidence intervals (CI) to assess differences in variant frequencies.
Results: The A10398G variant results in a threonine-to-alanine substitution at amino acid 114, while C10400T is a synonymous mutation. Both variants exhibited positive linkage disequilibrium and were significantly more frequent in T2D patients compared to controls (A10398G: 67.0% vs. 51.3%, OR = 1.929, P = 0.0026; C10400T: 65.5% vs. 48.1%, OR = 2.052, P = 0.0009). PolyPhen-2 predicted these variants as benign, though the amino acid change at A10398G may affect complex I function. The findings suggest these variants may be influenced by selective pressures related to regional environmental and dietary factors independent of aging, contributing to T2D pathogenesis.
Conclusions: These suggest the influence of regional environmental and dietary factors, genetic drift, and selection pressures on mtDNA variant distribution. In addition, findings underscore the importance of considering haplogroup background and population-specific dynamics in understanding mtDNA’s role in T2D susceptibility.

Keywords: mtDNA, m.10398A>G, m.10400C>T, genetic drift, type 2 diabetes