From genotype to structure: MBL2 exon 1 and promoter variants associated with cytomegalovirus seropositivity in acute lymphoblastic leukemia from the Brazilian Amazon

Abstract Background Variants in the MBL2 gene influence serum levels and structure of mannose-binding lectin (MBL) and may increase infection risk in immunocompromised individuals. We evaluated MBL2 exon 1 and promoter variants in relation to cytomegalovirus (CMV) and Epstein–Barr virus (EBV) seropositivity in patients with acute lymphoblastic leukemia (ALL) from Amazonas, Brazil, and modelled the structural impact of the exon 1 variants. Methods and results 107 patients with ALL and 76 controls were genotyped; CMV and EBV seropositivity was determined by ELISA, and exon 1 variants were analysed in silico with AlphaFold and DUET. CMV IgG associations were estimated by group using Firth logistic regression adjusted for age and sex. The exon 1 O allele was associated with higher CMV seropositivity in ALL (aOR 5.12, 95% CI 1.24–20.53; p = 0.025), whereas in controls the − 221 X allele (aOR 0.09, 95% CI 0.014–0.462; p = 0.003) and XY genotype (aOR 0.09; p = 0.003) were associated with lower seropositivity. No variant was associated with EBV, and expression-based haplotypes showed no association with either virus. Modelling predicted that the exon 1 substitutions destabilise the MBL monomer, consistent with impaired oligomerisation of the collagen-like region. Conclusions Against a background of high CMV seroprevalence, MBL2 variants showed context-dependent associations with CMV seropositivity. Structural modelling provides a plausible rationale for these exploratory associations, which require confirmation in larger cohorts.