# TLR9 gene polymorphism -1237T/C (rs5743836) is associated with low IgG antibody response against PvCSP variants in symptomatic P. vivax infections in Venezuela

## TL;DR

This study found that a specific genetic variation in the TLR9 gene is linked to lower antibody responses against malaria proteins in individuals infected with Plasmodium vivax in Venezuela.

## Contribution

The study identifies a novel association between the TLR9 gene polymorphism rs5743836 and reduced IgG antibody response against PvCSP variants in P. vivax infections.

## Key findings

- Heterozygous genotype T/C for TLR9 SNP rs5743836 is associated with lower IgG antibody response against PvCSP VK247 and V-like.
- High antibody responders to PvCSP variants reported fewer symptoms compared to medium and low responders.
- Over 90% of individuals had IgG antibodies against PvCSP variants and PvMSP-119.

## Abstract

Clinical immunity to malaria has been associated with humoral immune responses targeting asexual-stage parasite proteins. However, the variability in antibody-driven responses may be influenced by genetic factors in the human host. This study aimed to evaluate the frequency of SNPs in the TLR9 gene and their association with IgG antibody responses against PvCSP variants (VK247, VK210, and V-like) and PvMSP-119 among individuals presenting with symptomatic Plasmodium vivax infections in a malaria-endemic region of Venezuela.

A cross-sectional study was conducted in Bolívar state, Venezuela, involving 210 individuals infected with P. vivax. IgG reactivity against P. vivax recombinant antigens was assessed by ELISA, and three TLR9 gene SNPs (rs5743836, rs352140, and rs187084) were genotyped by PCR. The median age of individuals was 29 years, with the majority being male miners with a prior history of malaria. Over 90% of individuals exhibited IgG antibodies against the three PvCSP variants and PvMSP-119. High responders to the PvCSP variants reported fewer symptoms compared to medium (p < 0.001) and low (p < 0.001) responders. Among the analyzed SNPs, heterozygous genotypes were the most prevalent. Using an overdominant inheritance model, carrying the heterozygous genotype (T/C) for TLR9 gene SNP rs5743836 was associated with lower IgG antibody response against PvCSP VK247 (aOR = 0.26, 95% CI = 0.09 to 0.73, p = 0.0094) and PvCSP V-like (aOR = 0.37, 95% CI = 0.14 to 0.99, p = 0.047). No significant associations between inheritance models for the three SNPs and parasitemia were observed.

These findings suggest that TLR9 gene variability, particularly the heterozygous genotype for SNP rs5743836, may influence the IgG antibody response against PvCSP VK247 and V-like. Identifying genetic traits that impact immune response development could be valuable for malaria vaccine design and implementation.

In this study, we investigated how human genetic differences might affect the immune responses to malaria. Specifically, we looked at how certain genetic variations in the TLR9 gene, which is part of the immune system, might affect the production of antibodies against malaria proteins in 210 Venezuelan individuals infected with Plasmodium vivax, one of the parasites that causes malaria. Most of these individuals were male miners likely infected in a highly endemic area. Our findings suggest that people with a specific genetic variation, known as a heterozygous genotype in the TLR9 gene, had different levels of antibodies against two malaria proteins. Interestingly, those with higher antibody levels had fewer symptoms, suggesting that a stronger immune response may protect against malaria symptoms. Understanding these genetic influences on immune response could be valuable in designing vaccines and treatments that work more effectively in different populations.