Mutations of complement lectin pathway genes MBL2 and MASP2 associated with placental malaria

Ville Holmberg,Frank P Mockenhaupt,Seppo Meri,Päivi Onkamo,George Bedu-Addo,Päivi Lahermo,Elisa Lahtela

doi:10.1186/1475-2875-11-61

Abstract

BackgroundInnate immunity plays a crucial role in the host defense against malaria including Plasmodium falciparum malaria in pregnancy, but the roles of the various underlying genes and mechanisms predisposing to the disease are poorly understood.Methods98 single-nucletoide polymorphisms were genotyped in a set of 17 functionally related genes of the complement system in 145 primiparous Ghanaian women with placental malaria, defined by placental parasitaemia or malaria pigment, and as a control, in 124 non-affected primiparae.ResultsPlacental malaria was significantly associated with SNPs in the lectin pathway genes MBL2, MASP2, FCN2 and in properdin. In particular, the main African mannose-binding lectin deficiency variant (MBL2*G57E, rs1800451) increased the odds of placental malaria (OR 1.6; permuted p-value 0.014). In contrast, a common MASP2 mutation (R439H, rs12085877), which reduces the activity of MBL-MASP2 complexes occurred in 33% of non-affected women and in 22% primiparae with placental malaria (OR 0.55, permuted p-value 0.020).ConclusionsExcessive complement activation is of importance in the pathogenesis of placental malaria by mediating inflammation, coagulation, and endothelial dysfunction. Mutated MBL and MASP2 proteins could have direct intrinsic effects on the susceptibility to placental malaria, in addition to their roles in regulation of downstream complement activation.

Highlights

Innate immunity plays a crucial role in the host defense against malaria including Plasmodium falciparum malaria in pregnancy, but the roles of the various underlying genes and mechanisms predisposing to the disease are poorly understood
Toll-like receptors (TLRs), for instance, are crucial mediators of innate immunity to P. falciparum [10], and variant signalling as deduced from functionally relevant single nucleotide polymorphisms (SNPs) has been associated with an increased risk and/ or manifestation of malaria in pregnancy [11,12]
We mainly focused on SNPs with minor allele frequencies > 0.05 in both African and European populations based on HapMap data

Summary

Introduction

Innate immunity plays a crucial role in the host defense against malaria including Plasmodium falciparum malaria in pregnancy, but the roles of the various underlying genes and mechanisms predisposing to the disease are poorly understood. Toll-like receptors (TLRs), for instance, are crucial mediators of innate immunity to P. falciparum [10], and variant signalling as deduced from functionally relevant single nucleotide polymorphisms (SNPs) has been associated with an increased risk and/ or manifestation of malaria in pregnancy [11,12]. One third of the variability in susceptibility to placental malaria is thought to be due to host genetic factors [13] These may include the complement system, composed of three pathways, the classical, the lectin and the alternative pathway

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Results