Mitochondrial haplogroup A2 is associated with increased COVID-19 mortality in an admixed Brazilian population

Abstract

Mitochondria play a crucial role in cellular respiration and immune responses. Mitochondrial DNA (mtDNA) haplogroups and variants have been associated with various diseases, including COVID-19. This study analyzed complete mtDNA sequences from 467 Brazilian patients with COVID-19 to investigate associations between mtDNA ancestry and mortality risk. Using classical statistical methods and a machine learning model, we identified key contributors to outcomes, with age as the primary risk factor, followed by male sex. Several mtDNA variants-663G, 1736G, 2706G, 3010A, 4248C, 4824G, 8027A, 8794T, and 10873C-were significantly associated with increased mortality risk. Most are characteristic of haplogroup A2, prevalent in populations with Native American ancestry. Notably, the 8027A allele, a non-synonymous substitution (Alanine > Threonine at position 148 of Cytochrome C Oxidase II), was predicted to be potentially damaging and emerged as the most significant marker. Rather than being disease-causing, these variants may amplify risk through interactions with other genetic, environmental, and clinical factors. Our findings emphasize that mtDNA variants and haplogroups are not phenotypically neutral and could serve as biomarkers of COVID-19 severity. Genetic studies prioritizing Indigenous populations and their descendants, who may be particularly susceptible to certain viruses, are urgently needed, especially given the predominant focus on European populations.

Keywords: COVID-19; Haplogroup A2; Mitochondria; Native American; Pandemics; mtDNA.

Fig. 1

Frequency of mitochondrial DNA continental ancestry. Pie charts depicting the distribution of mtDNA continental ancestry in the overall dataset and within each COVID-19 case group (survivors and deceased).

Fig. 2

Frequency of mitochondrial macro-haplogroups by case group. Column chart showing the distribution of mtDNA macro-haplogroups across COVID-19 case groups (survivors and deceased).

Fig. 3

Adjusted multivariate logistic regression for macro-haplogroups. Bar chart displaying odds ratios (ORs) and 95% confidence intervals for variables that remained statistically significant in the multivariate regression model, which included mtDNA macro-haplogroups and clinical covariates. The dashed vertical line at OR = 1.0 indicates the null value (no association).

Fig. 4

Adjusted multivariate logistic regression for mitochondrial DNA variants. Bar chart displaying odds ratios (ORs) and 95% confidence intervals for variables that remained statistically significant in the multivariate logistic regression model, which included mtDNA variants and clinical covariates. The dashed vertical line at OR = 1.0 represents the null value (no association).

Fig. 5

Global feature importance based on mean SHAP values. Bar chart showing the average contribution of each feature to the model’s predictions, as measured by SHAP (SHapley Additive exPlanations) values. Age was the most influential variable, followed by specific comorbidities (hypertension and diabetes), sex, and other comorbidities (obesity and chronic conditions, including kidney-related and non-kidney-related diseases). Several mitochondrial DNA (mtDNA) variants—particularly 8027A, 2706G, 11914A, 3010A, 10873C, and 1736G—also contributed substantially, with the first three ranking above immunodeficiencies. The combined contribution of 88 additional mtDNA variants accounted for approximately 0.17, reflecting their collective impact on model predictions.