Pyruvate Kinase and Fcγ Receptor Gene Copy Numbers Associated With Malaria Phenotypes.

Genetic factors are associated with susceptibility to many infectious diseases and may be determinants of clinical progression. Gene copy number variation (CNV) has been shown to be associated with phenotypes of numerous diseases, including malaria. We quantified gene copy numbers of the pyruvate kinase, liver, and red blood cell (PKLR) gene as well as of the Fcγ receptor 2A and Fcγ receptor 2C (FCGR2A, FCGR2C) and Fcγ receptor 3 (FCGR3) genes using real-time quantitative polymerase chain reaction (RT-qPCR) assays in Gabonese children with severe (n = 184) or and mild (n = 189) malaria and in healthy Gabonese and white individuals (n = 76 each). The means of PKLR, FCGR2A, FCGR2C, and FCGR3 copy numbers were significantly higher among children with severe malaria compared to those with mild malaria (P < .002), indicating that a surplus of copies of those genes is significantly associated with malaria severity. Copy numbers of the FCGR2A and FCGR2C genes were significantly lower (P = .005) in Gabonese individuals compared with white individuals. In conclusion, CNV of the PKLR, FCGR2A, FCGR2C, and FCGR3 genes is associated with malaria severity, and our results provide evidence for a role of CNV in host responses to malaria.

Genetic evidence of functional ficolin-2 haplotype as susceptibility factor in cutaneous leishmaniasis.

BACKGROUND: Ficolin-2 coded by FCN2 gene is a soluble serum protein that plays an important role in innate immunity. In this study, we analyzed five functional polymorphisms of the FCN2 gene for their possible association with cutaneous leishmaniasis. METHODS: Initially we screened 40 Syrian Arabs for the entire FCN2 gene. We investigated the contribution of FCN2 functional variants in 226 patients with cutaneous leishmaniasis and 286 healthy controls from Syria. Polymorphisms in the promoter regions (-986G/A, -602G/A, -4A/G) of the FCN2 gene were assessed by TaqMan real time PCR, whereas polymorphisms in exon8 (+6359C/T and +6424G/T) were assessed by DNA sequencing. We also measured serum ficolin-2 levels in 70 control Syrian Arabs and correlated the serum concentrations to FCN2 genotypes and haplotypes respectively. RESULTS: Nine new FCN2 variants including two with non synonymous substitutions in exon6 and exon8 were observed. The homozygous genotypes +6424T/T were distributed more in controls and none in patients (P = 0.04). The AGACG haplotype were observed more in patients than in controls (OR = 2.0, 95%CI 1.2-3.4, P = 0.006). The serum ficolin-2 levels were significantly distributed among the reconstructed ficolin-2 haplotypes (P<0.008) and the haplotype AGACG was observed with higher ficolin-2 levels in 70 control individuals. CONCLUSION: Our results demonstrate a significant association of FCN2 AGACG haplotype with cutaneous leishmaniasis in a Syrian Arab population. These first results provide a basis for a future study that could confirm or disprove possible relationships between FCN2 gene polymorphisms with cutaneous leishmaniasis.

Ficolin-2 levels and genetic polymorphisms of FCN2 in malaria.

Human ficolin-2 (L-ficolin; FCN2) is a serum protein binding to sugar moieties of different human micro-pathogens forcing phagocytosis. Here, we investigate the clinical significance of FCN2 in African children with either mild or severe malaria (n = 130 and n = 108, respectively) from Gabon by analyzing three promoter SNPs (-986G>A, -602G>A, and -4A>G) and one single nucleotide polymorphisms (SNP) in exon 8 (+6424G>T) using quantitative TaqMan, real-time polymerase chain reaction (PCR). In addition, we measured the ficolin-2 plasma levels at two time points: on admission (t(0), acute disease) and 4 weeks after treatment (t(1), healthy phase). Comparison of ficolin-2 plasma levels shows that ficolin-2 concentration is highest during acute severe disease. In addition, we determined polymorphisms in the promoter and all coding regions of FCN2 in 40 Gabonese. Linkage disequilibrium data revealed polymorphic allelic combination patterns in the FCN2 promoter region; strong allelic combinations at -986 and -4, and -557 and -64 were found. No FCN2 promoter haplotypes were significantly distributed between mild and severe cases.

Interplay of host and infectious agents.

In this group we would like to answer the question why people show a different response against certain pathogens. In many infections the course of the disease can range from asymptomatic carriage to the severest forms even death. In the past we have analysed candidate genes and their role in the course of malaria and could detect some polymorphisms influencing infectious diseases in the genes encoding NOS2, MBL2, IFNa, FCN2, and receptors for IFNg and IFNa. Having worked initially mainly on malaria we broadened our spectrum also to other infectious diseases like hepatitis B, Leprosy, schistosomiasis. Here we give a short overview about ongoing projects.

Parasite-host interaction in malaria: genetic clues and copy number variation.

In humans, infections contribute highly to mortality and morbidity rates worldwide. Malaria tropica is one of the major infectious diseases globally and is caused by the protozoan parasite Plasmodium falciparum. Plasmodia have accompanied human beings since the emergence of humankind. Due to its pathogenicity, malaria is a powerful selective force on the human genome. Genetic epidemiology approaches such as family and twin studies, candidate gene studies, and disease-association studies have identified a number of genes that mediate relative protection against the severest forms of the disease. New molecular approaches, including genome-wide association studies, have recently been performed to expand our knowledge on the functional effect of human variation in malaria. For the future, a systematic determination of gene-dosage effects and expression profiles of protective genes might unveil the functional impact of structural alterations in these genes on either side of the host-parasite interaction.