# Genetic background and immune response in paracoccidioidomycosis: A systematic review and meta-analysis of single nucleotide variants

## TL;DR

This study reviews genetic factors that may influence susceptibility and severity of paracoccidioidomycosis, a neglected fungal disease in Latin America.

## Contribution

The study systematically reviews and meta-analyzes SNVs associated with paracoccidioidomycosis, highlighting limitations in current evidence.

## Key findings

- Variants in IL10 and VDR genes showed significant associations in individual studies but not in meta-analysis.
- Current evidence linking genetic variants to paracoccidioidomycosis is limited due to small sample sizes and methodological heterogeneity.
- Larger and better-designed studies are needed to confirm the role of genetic factors in disease susceptibility and outcomes.

## Abstract

Paracoccidioidomycosis (PCM) is a systemic fungal infection endemic to Latin America, especially Brazil, where it is considered a neglected occupational disease. Caused by Paracoccidioides spp., PCM presents a wide spectrum of clinical manifestations, ranging from localized to severe disseminated forms. This heterogeneity suggests that host-related factors, including genetic background, may influence disease development. Genetic susceptibility to infectious diseases is key to understanding differences in immune responses. In PCM, variants in immune-related genes such as cytokines and pattern recognition receptors may modulate susceptibility and disease progression. This study aimed to review the literature on the association between single nucleotide variants (SNVs) PCM susceptibility, severity, and clinical outcomes. A systematic review followed PRISMA guidelines, searching databases like MEDLINE (PubMed), Cochrane Library, LILACS, SciELO, Web of Science, and Google Scholar. Keywords related to “Paracoccidioidomycosis” and “SNVs” were used. The review included studies on SNVs and PCM susceptibility. The quality of the evidence was assessed with the Cochrane and Joanna Briggs Institute risk of bias tool. We also performed a meta-analysis of studies utilizing identical SNVs. This study is registered on PROSPERO, number CRD42025646417. Two SNVs, Interleukin 10 (IL10) and Vitamin D Receptor (VDR) showed a significant association in individual analyses, but none demonstrated a significant association in the meta-analysis. The main limitations discussed in the studies were insufficient sample size, population heterogeneity, and the composition of control groups. Although some SNVs, particularly in IL10 and VDR, showed significant associations with PCM susceptibility in individual studies, the evidence remains limited. The meta-analyses included only two studies per SNV, resulting in low statistical power and exploratory pooled estimates, largely reflecting small sample sizes, lack of replication, and methodological heterogeneity across studies.

Paracoccidioidomycosis is a fungal disease that affects mainly rural workers in Latin America, especially in Brazil, and remains largely neglected despite its social and health impact. People exposed to the fungus can develop different forms of the disease, from mild to severe, suggesting that individual biological factors play an important role. In this study, we asked whether genetic differences between people help explain who becomes ill and how severe the disease can be. We systematically reviewed published studies that investigated genetic variants in immune-related genes and their association with paracoccidioidomycosis. We also combined available data using meta-analysis when the same genetic variants were evaluated in more than one study. Although some studies suggested that variants in genes related to immune regulation and vitamin D signaling might influence susceptibility to the disease, these findings were not confirmed when the data were analyzed together. Our results show that current evidence linking human genetic variation to paracoccidioidomycosis is limited and inconsistent. Most studies included few participants and differed in their design, populations, and selection of control groups. We conclude that larger, better-designed studies are needed to clarify whether genetic factors truly influence the risk and clinical outcomes of this neglected fungal disease.