Abstract
BACKGROUND: Pneumonia is a major cause of mortality and health burden in children under five, yet its genetic etiology remains poorly understood. Methyltransferase 4, N6-adenosine (METTL4), is a methyltransferase enzyme responsible for RNA and DNA methylation and is known to be activated under hypoxic conditions. However, its potential link to susceptibility to pneumonia has not been evaluated. This study aimed to explore candidate regulatory single nucleotide polymorphisms (SNPs) within the METTL4 gene and their association with the development of severe pneumonia. RESULTS: In this study, we recruited a cohort of 1034 children with severe pneumonia and 8426 healthy controls. We investigated the associations of candidate regulatory single nucleotide polymorphisms (SNPs) within METTL4 polymorphisms with severe pneumonia. Our results indicated that the C allele of rs9989554 (P = 0.00023, OR = 1.21, 95% CI: 1.09-1.34) and the G allele of rs16943442 (P = 0.0026, OR = 1.22, 95% CI: 1.07-1.38) were significantly associated with an increased risk of severe pneumonia. The regulatory potential of these two SNPs in the lung was investigated using tools such as expression quantitative trait loci (eQTLs), RegulomeDB, and FORGEdb. CONCLUSIONS: This study represents the first investigation elucidating the role of genetic variations in the METTL4 gene and their influence on susceptibility to severe pneumonia in pediatric populations. METTL4 is identified as a novel predisposing gene for severe pneumonia and a potential therapeutic target. Further research is warranted to validate this correlation and to comprehensively elucidate the biological role of the METTL4 gene in severe pneumonia.