Immunomodulatory effects of the TIRAP/MAL rs8177374 (S180L) variant: Meta-Analytic evidence from severe and Plasmodium falciparum malaria.

BACKGROUND

The rs8177374 (S180L) polymorphism in TIRAP has been implicated in altered susceptibility to various infectious diseases, including malaria, though results across studies have been inconsistent.

OBJECTIVE

To systematically review and meta-analyze the association between the TIRAP/MAL rs8177374 polymorphism and malaria susceptibility, including severe malaria and Plasmodium falciparum infection.

METHODS

A systematic search of PubMed, Scopus, and Web of Science was conducted up to December 31, 2024, without language or geographic restrictions. Case-control and cohort studies reporting genotype and allele frequencies of rs8177374 in malaria patients and controls were included. Studies with control groups deviating from Hardy-Weinberg equilibrium were excluded. Two reviewers independently screened records, extracted data, and assessed study quality using the Newcastle-Ottawa Scale. Pooled odds ratios (ORs) with 95 % confidence intervals (CIs) were calculated under six genetic models using fixed- or random-effects meta-analyses. Heterogeneity was assessed with Cochran's Q and I2 statistics. Sensitivity analyses were performed using a leave-one-out approach. Publication bias was assessed using Egger's and Begg's tests.

RESULTS

Ten studies comprising 4103 malaria cases and 2460 controls were included. No significant association was observed between rs8177374 and overall malaria susceptibility under any genetic model. In contrast, the T allele and heterozygous genotypes (TC) were consistently associated with a lower risk of severe malaria (T vs. C: OR = 0.51, 95 % CI: 0.40-0.65, p < 0.001). Conversely, in the P. falciparum subgroup, the variant was linked to an increased risk of infection (T vs. C: OR = 1.47, 95 % CI: 1.09-1.98, p = 0.012). Sensitivity analyses confirmed the stability of these associations, and no single study significantly influenced the pooled estimates.

LIMITATIONS: Limited number of studies in subgroup analyses, high heterogeneity in several comparisons, and geographic restriction to Asian and African populations.

CONCLUSIONS

The rs8177374 polymorphism is not associated with overall malaria or P. falciparum malaria, but shows a protective effect against severe malaria. These results support a modulatory role of TIRAP/MAL in malaria pathogenesis and warrant further functional and multi-ethnic studies.