# Genetic ancestry proportion influences risk of adverse events from tuberculosis treatment in Brazil

## TL;DR

This study found that genetic ancestry influences the risk of adverse drug reactions in tuberculosis patients in Brazil, with African ancestry linked to lower risk and European ancestry to higher risk.

## Contribution

The study demonstrates that genetic ancestry proportions are significant predictors of adverse drug reactions in TB treatment outcomes in a diverse Brazilian population.

## Key findings

- Increased African ancestry proportion was associated with decreased risk of Grade 2+ adverse drug reactions.
- Higher European ancestry proportion was linked to increased risk of Grade 2+ adverse drug reactions.
- A significant interaction was observed between HIV status and African ancestry in relation to adverse drug reactions.

## Abstract

Tuberculosis (TB) treatment is highly effective, but response to therapy varies by geography and population subgroups. We assessed differences in TB treatment response in a representative and heterogeneous Brazilian population. We estimated genetic ancestry according to major genetic ancestry groups (African, European, and Amerindian) in the Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil cohort using ADMIXTURE software. RePORT-Brazil is an observational prospective cohort study of individuals with newly-diagnosed, culture-confirmed, pulmonary TB. Outcomes attributed to TB treatment included Grade 2 or higher adverse drug reaction (ADR), Grade 3 or higher ADR, hepatic ADR, and failure/recurrence. Genetic ancestry proportions were evaluated as predictors in univariate and multivariable logistic regression models for each outcome, and in stratified models for each genetic ancestry group. There were 930 pulmonary TB patients included in this study. In multivariable models we observed a decreased risk of Grade 2 + ADR when African ancestry proportion increased by 10% (Odds Ratio [OR] 0.41, 95% Confidence Interval [CI] 0.20–0.85) and an increased risk for Grade 2 + ADR with increasing European genetic ancestry (OR 2.33, 95% CI 1.14–4.76). In secondary analyses evaluating the interaction of HIV and genetic ancestry, we observed a statistically significant interaction between HIV and African genetic ancestry, but significantly decreased risk for Grade 2 + ADR with increasing African ancestry proportion. There were no associations with Amerindian genetic ancestry or for other treatment outcomes. In this Brazilian TB cohort, increased toxicity risk was associated with decreased African and increased European ancestry proportion.

The online version contains supplementary material available at 10.1007/s00439-025-02809-y.