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Genetic susceptibility and resistance to Schistosomiasis . By: Bashir Alsiddiq Amal Badawi. Human Schistosomiasis. Is parasitic disease which caused by Schistosoma species mainly include: 1- Schistosoma haematobium 2- Schistosoma mansoni 3- Schistosoma japonicum
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Genetic susceptibility and resistance to Schistosomiasis • By: • Bashir Alsiddiq • Amal Badawi
Human Schistosomiasis • Is parasitic disease which caused by Schistosoma species mainly include: 1- Schistosoma haematobium 2- Schistosoma mansoni 3- Schistosoma japonicum • Approximately 300 million people are exposed to Schistosomain 74 countries worldwide with a concentrationin Asia, Africa, and South America Each year 280,000 people die of this disease.
Immunology • The following agent used by human to protect against Schistosomisis (Antibodies, Complement, Eosinophils and Cytokines) • The immunity is mainly drive by Th2 response. • The most important mechanisms against Schistosoma is ADCC (Antibody dependant cell mediated cytotoxicity).
Immunopathology • Cercarial dermatitis is due to hypersensitivity reactions. • Katayama syndrome is due to immune complex formation. • Chronic Schistosomiasis is due to granuloma formation whish is followed by Fibrosis and then severe complications.
Factors involved in Schistosomiasis • Schistosomiasis is a multifactorial disease involving number of factors include: • environmental. • Behavioral. • Parasitic. • vector. • host factors (Genetic factor and Immunity)
Genetic susceptibility • We can classify into: • Genetic susceptibility to Schistosomiasis infection. • Genetic susceptibility to Schistosomiasis complications.
Genetic susceptibility and resistance to Schistosomiasis infection
In 1991, Dessein et al. performed segregation analysis,the first step to determine the mode of inheritance of a given trait from family data, on 20 Brazilian pedigrees (269 individuals), issued from an endemic area of S.m., in the aim toinvestigate whether a major gene controls human susceptibility/resistance to infection by Schistosoma.
The deleterious allele occurs with a frequency of 0.16 (A). This frequency correlates: • 3% of AA predisposed to high infections • 27% of Aa with an intermediate level of infection • 70% of aa the population resistant.
To localize the major gene involved in the control of infection by Schistosoma, referred as SM1, the authors also carried out a genome-wide study on 142 Brazilian subjects belonging to 11 informative families pedigrees. • In a primary map (246 markers; interval of 15cM between adjacent markers). Desseinet al, 1999
SM-1 region: Contains several candidate genes involved in the regulation of the immune response to Schistomiasis: • The genes encoding for the interleukins 4 (IL-4), IL-5, IL-9, and IL-13.(Th2 response). • The region also contains the gene encoding for the IL12p40 subunit common to the proinflammatory cytokines IL12 and IL23. • the Interferon Regulatory Factor 1 (IRF1), which encodes a transcriptional activator of interferonα and β. • the Colony-Stimulating Factor 1 Receptor (CSF1R) gene
Linkage analysis • two adjacent markers on chromosome 5q31-33, D5S393 and D5S410, provided lod scores greater than 1.9, indicating a suggestive linkage. • Significant evidence of linkage was obtained with 2 proximal markers: D5S636 and the Colony Stimulating Factor-1 Receptor (CSF1R), provided lod scores = 5.45 • This result was confirmed later in an independent study done in a Senegalese population living in an endemic area for S.m.
Marquetet al 1999,found that four additional markers in three other regions provided interesting lod-score values above 0.83: • 1p22.2 with D1S216 (Zmax=+0.91) which contain candidate gene= The IL12 receptorβ2 chain gene is located close to the 1p22.2 region ,and plays an important role in the regulation of the Th1-type immune response.
B.21q22- qter with D21S1259 (Zmax=+1.09) which contain candidate gene= The interferon-beta receptor (IFN-βR) and interferon-alpha receptor (IFN-αR) genes.
C. the two adjacent markers D7S483 (Zmax=+0.91) and D7S550 (Zmax=+1.02,) in the 7q36 region. which contain candidate gene= the beta T cell receptor (TCRβ) gene maps closed to the 7q36 region
IL13 • The study was performed in two Dogon villages in Mali, where Schistosoma haematobium is endemic. • Associations were tested using family-based association tests and logistical regression analysis. • The alleles IL13-1055C (p 0.05) rs1800925 and IL13-591A (p 0.01) rs2069743 and IL13-1258 are shown, by family-based association test, to be preferentially transmitted to children with the 10% highest infections.
The result shows IL13-1055 C/C, C/T and T/T genotypes, age, gender, and village of residency, applied to the whole study population, showed that subjects bearing the IL13-1055T/T genotype were on average much less infected than individuals with other genotypes. • So IL13-1055T/T gene protect against schistosomiasis .(BouremaKouribaet al, 2005)
IL4 and IL5 • There is polymorphism in the IL4 promoter (IL4-590C/T) and also there is another polymorphism in IL5 promoter (IL5-202G/A). • Need further study to show the association of these polymorphism with Schistosomiais.
STAT 6 • Another study carried By logistic regression analysis, they found an association between (SNP) in the STAT6 gene (rs324013) and infection levels (P=0.04).They confirmed this association in analyses restricted to subjects under 20 years age and living in Boul. • They found rs324013C/T associated with highest infection level than other alleles.
Also they detected an additive effect of the rs324013 significant association between rs324013C/T and the highest infection levels and rs1800925 polymorphisms (P=0.005). (Isnard A et al, 2008).
FCER1A • In a genome-wide association study (GWAS), SNPs for association with serum IgE levels from the population-based study. • Functional variants in the gene encoding the alpha chain of the high affinity receptor for IgE (FCER1A) on chromosome 1q23 (A/C rs2251746 and C/G rs2427837) Alleles were strongly associated with efficacy IgE.
Polymorphisms within the RAD50 gene (rs2706347) on chromosome 5q31 were consistently associated with IgE levels. • Also there is disequilibrium (LD) block which encompasses the entire RAD50 gene and extends into the promoter region of the IL13, whereas rs20541 showed low levels of LD with RAD50 variants. (Stephan Weidingeret al, 2008)
Genetic Susceptibility And Resistance to schistosomiasis complications
SM2 In Sudan, 2-10% of infected subjects with S.mansoni die from periportalhepatic fibrosis in endemic region of the Schistosomiasis. Severe hepatic fibrosis occurs more frequent in certain families and absent in others despite the fact that all families had been living for years in the same conditions of infection (Mohammed Ali et al 1999).
SM2 Linkage analysis done for four candidate regions : Chromosome region 5q31-q33. HLA TNF region 6p21. Chromosome region 12q15. Chromosome region 6q22-q23.
SM2 • shows that this major locus maps to 6q22-q23 and its closely linked (multipoint LOD score 3.12) to INFGR1 gene encoding receptor of antifibrogenic cytokine IFNɣ. • This result suggests that polymorphism within the IFNGR1 gene could determine severity of hepatic disease due to S.mansoni ,
Cont….. and that IFNGR1 gene is strong candidate for the control of abnormal fibrosis observed in other disease such as tuberculosis (Pierre-Audigier et al., 1997; Roesler et al., 1999) • So SM2 in 6q22-q23 influencing disease progression with a possible involvement in the regulation of IFN-gamma. • This results will stimulate new strategies in drug and vaccine development (Alain J. Dessein et al 1999)
IFNGR1 • Two polymorphisms located in the third intron of the IFN-gamma gene are associated with periportal fibrosis (PPF). • These two polymorphisms are not in linkage disequilibrium ( p 0.246). • The IFN-gamma +2109 A/G polymorphism is associated with a higher risk for developing PPF.s • whereas the IFN-gamma +3810 G/A polymorphism is associated with less PPF.
IFNGR1 • These results are consistent with the results of previous studies. Indeed, PPF is controlled by a major locus located on chromosome 6q22-q23, closely linked to the gene encoding the alpha-chain of the IFN-gamma receptor, and low IFN-gamma producers have been shown to have an increased risk of severe PPF. (Chevillard et al, 2003).
HLA class II • In endemic area of S.japonicumin China, there are associations between host genetic factors and the onset of liver fibrosis. • Two HLA-DRB1 alleles, HLA-DRB1*0901 (P=0.012) and *1302 (P=0.039), and two HLA-DQB1 alleles, HLA-DQB1*0303 (P=0.012) and *0609 (P=0.037), were found to be significantly associated with susceptibility to fibrosis. • These associated DRB1 and DQB1 alleles are in very strong linkage disequilibrium, with DRB1*0901-DQB1*0303 and DRB1*1302-DQB1*0609 found as common haplotypes in this population.
HLA class II • The alleles HLA-DRB1*1501 (P=0.025) and HLA-DQB1*0601 (P=0.022) were found to be associated with resistance to hepatosplenic disease. • The alleles DQB1*0303 and DRB1*0901 did not increase susceptibility in the presence of DQB1*0601, indicating that DQB1*0601 is dominant over DQB1*0303 and DRB1*0901. (Mcmanus DP et al, 2001)