This study provides, for the first time, the characterization of exon 1 polymorphism of the MBL2 gene and investigates its potential association with serum MBL levels and susceptibility to infections in individuals living with ALL in the state of Amazonas, Brazil.
Our findings showed a higher frequency of the MBL*A allele and a lower frequency of the MBL*B allele within the study population. A recent study conducted in Istanbul, Turkey, found frequencies of MBL*A alleles (0.82) and MBL*B alleles (0.17) in ALL patients, but no statistically significant differences were observed compared to healthy individuals (Oguz et al., 2023). Another study that analyzed the allelic frequency of the MBL2 gene in Swedish adults with febrile neutropenia who were undergoing chemotherapy also found a higher frequency of the MBL*A allele (0.64). However, unlike our data, they observed a low frequency of the variant MBL*D allele (0.11) (Wong et al., 2012). Despite the variation in genetic backgrounds and geographical contexts among the study populations, both our study and the two previously referenced studies have identified a consistent pattern: a higher prevalence of the MBL*A allele and a lower prevalence of the MBL*B allele in patients. However, it is important to note that this shared trend is more likely due to population genetic background than to ALL itself.
The MBL*C variant was not identified in this study, similar to previous research conducted in the northern region of Brazil (Pontes et al., 2005). The absence or low frequency of the MBL*C variant in the Amazonian region could be due to specific genetic and evolutionary factors, such as the historical admixture between European, African, and indigenous ethnic groups (Edge & Rosenberg, 2015; Esteves Agostinho, 2020). However, further studies are necessary to comprehensively assess this situation. Our findings provide important insights into the frequencies of the MBL*A, MBL*B, and MBL*D alleles in the study population. These findings have important implications for future studies of host genetic variation in hematological diseases and could lead to improved clinical management of patients, especially those with genotypes associated with low MBL levels. This association with variants of the MBL2 gene could be particularly relevant in the context of ALL patients undergoing chemotherapy treatments (Cedzyński & Świerzko, 2020; Yen et al., 2017). Our findings revealed the O polymorphic allele (B or D) were more frequent in young patients (1–10 years old). While the frequency of an allele is not inherently linked to age, the presence of MBL structural gene mutation in homozygous or heterozygous form may directly impact disease course and prognosis in young patients by amplifying existing immunosuppression. Further research is needed to better understand the direct influence of MBL gene variants on ALL development.
Upon analyzing the genotype frequencies, it was observed that the A/O genotype exhibited the highest prevalence within the study population (0.49), whereas 63% of individuals carried the A/D genotype and 45% carried the A/B genotype. The A/A genotype had a frequency of 0.13, while the O/O genotype occurred in 38% of the individuals. The genotype frequencies found in our study differ from those reported in previous studies conducted with individuals suffering from different neoplastic hematological disease. For example, a study of patients with myeloid leukemia in Turkey found that the A/A genotype was more frequent (0.64) than the O/O genotype (0.17) (Sokołowska et al., 2020). Another study of patients with multiple myeloma conducted in Polish found that the A/A genotype (0.73) and B/B genotype (0.88) were more frequent than the O/O genotype (0.19) (Pehlivan et al., 2021). In this study, we observed a significantly lower frequency of the B/B genotype (0.08) than the frequencies reported in the aforementioned studies. This difference could be attributed to a number of factors, including the genetic composition of the population, the specific characteristics of our study group, and the overall diversity within the study population.
MBL exon 1 genotypes have been associated with increased susceptibility to infections throughout the years. Patients carrying the A/O genotype, particularly A/D, exhibited higher infection frequencies. Pana et al. (2014) identified a statically significant association between MBL2 gene A/O variants and an increased susceptibility to bacterial infections in children with B-cell acute lymphoblastic leukemia (Pana et al., 2014). In another study, a link was demonstrated between the A/O and O/O genotypes and an increased risk of febrile neutropenia or infections in oncohematological patients undergoing chemotherapy (Frakking et al., 2011). In a study carried out in South Africa, it was observed that MBL2 gene polymorphisms were associated with increased susceptibility to infection and humoral IgG response to C. trachomatis infection (p = 0.048) (Verweij et al., 2022). In this other study, an association of polymorphisms in codon 54 (A/B or B/B) was observed with the development of more severe symptoms of COVID-19 in children in a Turkish city (Yilmaz et al., 2023). Molle et al. (2006) found that multiple myeloma (MM) patients with the A/A genotype had a reduced risk of septicemia after autologous stem cell transplantation (Mølle et al., 2006). Although our study did not establish a statistically significant association between the A/O genotype and infection susceptibility, the higher number of infections observed in patients carrying this genotype suggests its clinical significancy in increasing susceptibility to infection in the context of ALL.
Our findings suggested that the O/O genotype might be associated with susceptibility to viral infections. Similar findings were found in research conducted in Morocco, which revealed a significant increase in susceptibility to HIV-1 infection in individuals carrying the O/O genotype (Bouqdayr et al., 2023). Another study evaluating the influence of MBL2 gene on susceptibility to Dengue (DENV) infection in a Vietnamese population, observed that the frequency of the O/O genotype was significantly higher among dengue patients, suggesting that this genotype is associate with the susceptibility to DENV infection (N. T. Giang et al., 2020). Although our results showed a significant association between the O/O genotype and susceptibility to viral infections, this association was not statistically strong. Further studies with larger numbers of individuals are necessary to better elucidate the role of the O/O genotype on infection susceptibility in the context of ALL.
While no correlation was found between serum MBL levels and MBL2 gene polymorphisms in this study, the observed serum MBL levels in the study group (mostly < 500 ng/mL) were considerably lower than the typical levels found in the general population (> 2000 ng/mL) (Baioumy et al., 2021; Izakovicova et al., 2023; Pehlivan et al., 2021). This suggests a serum MBL deficiency among ALL patients, regardless of their genotype.
Previous studies have reported a direct association between serum MBL levels and increased susceptibility to infections. A Merlen et al. (2015) demonstrated that the use of L-asparaginase therapy resulted in a reduction of serum MBL protein levels. This decrease was associated with a higher risk of thrombotic and infectious events in ALL patients (Merlen et al., 2015). Furthermore, a study carried out in Brussels, Belgium involving 255 oncohematological patients undergoing 569 chemotherapy cycles unveiled a heightened prevalence of infectious manifestations in comparison with healthy individuals (Vekemans et al., 2007). These results highlight the complex relationship between MBL protein levels and susceptibility to infections. Our findings underscore the importance of monitoring MBL levels as a potential predictor of infection risk in this clinical setting, especially in ALL patients, who have many factors that can affect MBL levels.
This study presents some limitations. For example, the size of study population may have affected the correlation between the MBL2 gene polymorphism and susceptibility to infections. However, the number of individuals enrolled in this study is relatively high, given that we are working with ALL patients, who are difficult to recruit in large numbers. It is also important to mention that the access to patient clinical records was limited. This included detailed information about medical history, immunological status, and treatments. In most cases, the information was incomplete, which impaired further analyses. Besides limitations, this study contributes to the scientific knowledge of the immunogenetic profile of the study population and may provide valuable insights for future investigations into how the innate immune system's interplay with clinical aspects of ALL