Exploring association between MBL2 gene polymorphisms and the occurrence of clinical blackwater fever through a case\u2013control study in Congolese children

Joseph M Bodi,Pierre M Tshibassu,Prosper T Lukusa,Ahmeddin H Omar,Aimé Lumaka,Kenji Hirayama,Michel N Aloni,Célestin N Nsibu,Jan Verhaegen,Roland L Longenge,Pierre Z Akilimali,Patrick K Kayembe

doi:10.1186/s12936-020-3100-8

Abstract

BackgroundBlackwater fever (BWF), one of the most severe and life-threatening forms of falciparum malaria, is characterized by acute massive intravascular haemolysis, often leading to acute renal failure. Thus far, the genetics of the underlying susceptibility to develop BWF is not fully elucidated. Deficiency in the MBL protein, an important component of the innate immune system, has previously been suggested to be a susceptibility factor for the development of severe malaria. This study aimed to evaluate the association between MBL2 gene polymorphisms, known to affect the MBL protein level/activity, and the occurrence of BWF among Congolese children.MethodsThis is a case–control study. Cases were patients with BWF, whereas controls, matched for gender and age, had uncomplicated malaria (UM). Dried blood spot was collected for genotyping.ResultsA total of 129 children were screened, including 43 BWF and 86 UM. The common allele in BWF and UM was A, with a frequency of 76.7 and 61.0%, respectively (OR: 2.67 (0.87–829) and p = 0.079). The frequency of the C allele was 18.6 and 29.1% in BWF and UM groups, respectively, with p = 0.858. Not a single D allele was encountered. Genotype AA was at higher risk for BWF whereas genotypes A0 (AB and AC) were over-represented in UM group (OR: 0.21 (0.06–0.78)) with p = 0.019. Nine haplotypes were observed in this study: 3 high MBL expression haplotypes and 6 low MBL expression haplotype. One new haplotype HYPC was observed in this study. None of these haplotypes was significantly associated with BWF.ConclusionThis pilot study is a preliminary research on MBL2 gene and infectious diseases in DRC. The study results show a higher risk for BWF in AA. This suggests that future studies on BWF should further investigate the contribution of a strong immune response to the occurrence of BWF.

Highlights

Blackwater fever (BWF), one of the most severe and life-threatening forms of falciparum malaria, is characterized by acute massive intravascular haemolysis, often leading to acute renal failure
Design and setting This study aimed to test the association between Mannose Binding Lectin gene (MBL2) polymorphisms and Blackwater fever, one of the most severe complications of malaria, and provide the first distribution data for MBL2 haplotypes in Congolese individuals
Using a non-conditional model, a binary logistic regression, including covariant, anti-malaria drugs, MBL2 gene polymorphism, G6PD and parasitaemia, it was observed that MBL2*AB or AC is protective factor in the development of BWF

Summary

Introduction

Blackwater fever (BWF), one of the most severe and life-threatening forms of falciparum malaria, is characterized by acute massive intravascular haemolysis, often leading to acute renal failure. Deficiency in the MBL protein, an important component of the innate immune system, has previously been suggested to be a susceptibility factor for the development of severe malaria. Three non-synonymous single nucleotide substitutions in the exon 1 of MBL2 gene cause dramatic decrease of MBL in heterozygous state or almost complete absence of MBL in homozygous or compound heterozygous state. Based on the classic MBL2 polymorphisms codification, substitutions at codons 52, 54 and 57 are referred to as D, B and C derived alleles, respectively, whereas the ancestral allele is known as allele A [10] Because these three variant alleles cause similar MBL deficiency, the concept of ‘O’ allele is used to describe either of these variants [8]

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