MtDNA variations at C5178a and A249d decrease the risk of severe COVID-19 in a Han Chinese population from Central China

Abstract Background: Mitochondria have been shown to play vital roles during SARS-CoV-2 infection and COVID-19 development. Currently, whether mitochondrial DNA (mtDNA) variations, which define mtDNA haplogroups and determine OXPHOS performance and ROS production, are associated with COVID-19 risk is unclear. Methods: A population-based case-control study was conducted to compare the distribution of mtDNA variations defining mtDNA haplogroups between healthy controls (n = 615) and COVID-19 patients (n = 536). COVID-19 patients were diagnosed based on molecular diagnostics of the viral genome by qPCR and chest X-ray or computed tomography (CT) scanning. The exclusion criteria for the healthy controls were any history of diseases in the one-month preceding study assessment. MtDNA variations defining mtDNA haplogroups were identified by PCR-RFLPs and HVS-I sequencing and determined based upon mtDNA phylogenetic analysis using Mitomap Phylogeny. Student’s t-test was used for continuous variables, and Pearson’s chi-squared test or Fisher’s exact test was used for categorical variables. To assess the independent effect of each mtDNA variation defining mtDNA haplogroups, multivariate logistic regression analyses were performed to calculate the adjusted odds ratios (ORs) and 95% confidence intervals (CIs) with adjustments for the possible confounding factors of age, sex, smoking and diseases (including cardiopulmonary diseases, diabetes, obesity and hypertension) determined through clinical and radiographic examinations. Results: Multivariate logistic regression analyses revealed that mtDNA variations at C5178a and A249d were associated with a reduced risk of severe COVID-19 (OR = 0.590, 95% CI = 0.428-0.814, p = 0.001; and OR = 0.654, 95% CI = 0.457-0.936, p = 0.020, respectively), while A4833G, A4715G, T3394C and G5417A/C16257a/C16261T were related to an increased risk of severe COVID-19 (OR = 2.336, 95% CI = 1.179-4.608, p = 0.015; OR = 2.033, 95% CI = 1.242-3.322, p = 0.005; OR = 3.040, 95% CI = 1.522-6.061, p = 0.002; and OR = 2.890, 95% CI = 1.199-6.993, p = 0.018, respectively). Conclusion: mtDNA variations C5178a and A249d might contribute to an individual’s resistance to developing severe COVID-19, whereas A4833G, A4715G, T3394C and G5417A/C16257a/C16261T might increase an individual’s risk of developing severe COVID-19. Trial registration: no.