Mannose-binding lectin and susceptibility to schistosomiasis.

BACKGROUND: Human ficolin 2 (encoded by FCN2) and mannose-binding lectin (encoded by MBL2) bind to specific pathogen-associated molecular patterns, activate the complement lectin cascade in a similar manner, and are associated with several infectious diseases. Our recently published study established certain FCN2 promoter variants and ficolin-2 serum levels as protective factors against schistosomiasis. METHODS: We used the Nigerian cohort from our recently published study, which included 163 Schistosoma haematobium-infected individuals and 183 matched healthy subjects, and investigated whether MBL deficiency and MBL2 polymorphisms are associated with schistosomiasis. RESULTS: MBL serum levels were significantly higher in controls and were associated with protection (P < .0001). The -550H minor allele was significantly associated with protection (P = .03), and the heterozygous genotypes -550HL were observed to confer protection (P = .03). The MBL2*HYPA haplotype was significantly associated with protection (P = .03), with significantly higher serum MBL levels in controls (P = .00073). The heterozygous 6-bp deletion in the promoter was observed to be a susceptibility factor in schistosomiasis (P = .03). CONCLUSIONS: In agreement with findings from our recently published study, the findings reported here support the observation that MBL is also associated with protection in schistosomiasis.

Ficolin-2 levels and FCN2 genetic polymorphisms as a susceptibility factor in schistosomiasis.

BACKGROUND: Human ficolin-2 (L-ficolins) encoded by the FCN2 gene are pattern-recognition proteins involved in innate immunity and are associated with several infectious diseases. METHODS: A Nigerian cohort of 168 Schistosoma haematobium-infected individuals and 192 healthy controls were examined for functional single-nucleotide polymorphisms in the promoter region (-986G>A, -602G>A, -4A>G) and in exon 8 (+6424G>T) using real-time polymerase chain reaction. RESULTS: The FCN2 -986A and -4G alleles were significantly associated with the occurrence of schistosomiasis (P = .0004 for -986G>A; P = .0001 for -4A>G). The heterozygous genotypes (P = .0006 for -986G>A; P = .0002 for -4A>G) were observed to be a risk factor for susceptibility to schistosomiasis, whereas the homozygous genotypes of major alleles (P = .0002 for -986G>A; P = .0001 for -4A>G) were observed to shield against schistosomiasis. The haplotype AGGG (P = .0002) was observed to be a risk factor for susceptibility to schistosomiasis compared with controls, and the haplotype GGAG (P = .04) was observed to confer protection compared with patients. Ficolin-2 serum level was significantly higher in controls (P < .005) and in controls with GGAG haplotypes (P < .0001). CONCLUSIONS: Our findings demonstrate that FCN2 promoter variants (-986G>A and -4A>G) influence ficolin-2 serum levels and susceptibility to schistosomiasis.

Reliable and rapid characterization of functional FCN2 gene variants reveals diverse geographical patterns.

BACKGROUND: Ficolin-2 coded by FCN2 gene is a soluble serum protein and an innate immune recognition element of the complement system. FCN2 gene polymorphisms reveal distinct geographical patterns and are documented to alter serum ficolin levels and modulate disease susceptibility. METHODS: We employed a real-time PCR based on Fluorescence Resonance Energy Transfer (FRET) method to genotype four functional SNPs including -986 G > A (#rs3124952), -602 G > A (#rs3124953), -4A > G (#rs17514136) and +6424 G > T (#rs7851696) in the ficolin-2 (FCN2) gene. We characterized the FCN2 variants in individuals representing Brazilian (n = 176), Nigerian (n = 180), Vietnamese (n = 172) and European Caucasian ethnicity (n = 165). RESULTS: We observed that the genotype distribution of three functional SNP variants (-986 G > A, -602 G > A and -4A > G) differ significantly between the populations investigated (p < 0.0001). The SNP variants were highly linked to each other and revealed significant population patterns. Also the distribution of haplotypes revealed distinct geographical patterns (p < 0.0001). CONCLUSIONS: The observed distribution of the FCN2 functional SNP variants may likely contribute to altered serum ficolin levels and this may depend on the different disease settings in world populations. To conclude, the use of FRET based real-time PCR especially for FCN2 gene will benefit a larger scientific community who extensively depend on rapid, reliable method for FCN2 genotyping.

Ficolin-2 levels and FCN2 haplotypes influence hepatitis B infection outcome in Vietnamese patients.

Human Ficolin-2 (L-ficolins) encoded by FCN2 gene is a soluble serum protein that plays an important role in innate immunity and is mainly expressed in the liver. Ficolin-2 serum levels and FCN2 single nucleotide polymorphisms were associated to several infectious diseases. We initially screened the complete FCN2 gene in 48 healthy individuals of Vietnamese ethnicity. We genotyped a Vietnamese cohort comprising of 423 clinically classified hepatitis B virus patients and 303 controls for functional single nucleotide polymorphisms in the promoter region (-986G>A, -602G>A, -4A>G) and in exon 8 (+6424G>T) by real-time PCR and investigated the contribution of FCN2 genotypes and haplotypes to serum Ficolin-2 levels, viral load and liver enzyme levels. Haplotypes differed significantly between patients and controls (P = 0.002) and the haplotype AGGG was found frequently in controls in comparison to patients with hepatitis B virus and hepatocellular carcinoma (P = 0.0002 and P<0.0001) conferring a protective effect. Ficolin-2 levels differed significantly between patients and controls (p<0.0001). Patients with acute hepatitis B had higher serum Ficolin-2 levels compared to other patient groups and controls.The viral load was observed to be significantly distributed among the haplotypes (P = 0.04) and the AAAG haplotype contributed to higher Ficolin-2 levels and to viral load. Four novel single nucleotide polymorphisms in introns (-941G>T, -310G>A, +2363G>A, +4882G>A) and one synonymous mutation in exon 8 (+6485G>T) was observed. Strong linkage was found between the variant -986G>A and -4A>G. The very first study on Vietnamese cohort associates both Ficolin-2 serum levels and FCN2 haplotypes to hepatitis B virus infection and subsequent disease progression.

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.