Genetic analysis of human predisposition to hepatosplenic disease caused by schistosomes reveals the crucial role of connective tissue growth factor in rapid progression to severe hepatic fibrosis

Dessein, Alain; Arnaud, Violaine; He, Hongbin; Li, J.; Dessein, Hélia; Hou, Xin; Luo, Xinsong; Li, Y.

doi:10.1016/j.patbio.2013.01.005

Cited by 16 publications

(9 citation statements)

References 52 publications

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“…Though of interest, as APOE alleles are suggested to affect fibrosis progression in hepatitis C infection [26], [37], a much larger patient population would be needed to ensure adequate power for subtle genotype effects [35]. Gene studies of individuals infected with schistosomiasis have found significant associations of cytokines related to the immune response [38]–[40]. However, to date and similar to our result, no study has reported a link between the APOE gene polymorphism and schistosomiasis prevalence or severity.…”

Section: Discussionsupporting

confidence: 68%

Human Plasma Lipid Modulation in Schistosomiasis Mansoni Depends on Apolipoprotein E Polymorphism

et al. 2014

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BackgroundSchistosomiasis mansoni is a parasitic liver disease, which causes several metabolic disturbances. Here, we evaluate the influence of Apolipoprotein E (APOE) gene polymorphism, a known modulator of lipid metabolism, on plasma lipid levels in patients with hepatosplenic schistosomiasis.Methodology/Principal FindingsBlood samples were used for APOE genotyping and to measure total cholesterol (TC), LDL-C, HDL-C and triglycerides. Schistosomiasis patients had reduced TC, LDL-C and triglycerides (25%, 38% and 32% lower, respectively; P<0.0001) compared to control individuals, whereas HDL-C was increased (10% higher; P = 0.0136). Frequency of the common alleles, ε2, ε3 and ε4, was similar (P = 0.3568) between controls (n = 108) and patients (n = 84), implying that APOE genotype did not affect susceptibility to the advanced stage of schistosomiasis. Nevertheless, while patient TC and LDL-C levels were significantly reduced for each allele (except TC in ε2 patients), changes in HDL-C and triglycerides were noted only for the less common ε2 and ε4 alleles. The most striking finding, however, was that accepted regulation of plasma lipid levels by APOE genotype was disrupted by schistosomiasis. Thus, while ε2 controls had higher TC and LDL-C than ε3 carriers, these parameters were lower in ε2 versus ε3 patients. Similarly, the inverse relationship of TG levels in controls (ε2>ε3>ε4) was absent in patients (ε2 or ε4>ε3), and the increase in HDL-C of ε2 or ε4 patients compared to ε3 patients was not seen in the control groups.Conclusion/SignificanceWe confirm that human schistosomiasis causes dyslipidemia and report for the first time that certain changes in plasma lipid and lipoprotein levels depend on APOE gene polymorphism. Importantly, we also concluded that S. mansoni disrupts the expected regulation of plasma lipids by the different ApoE isoforms. This finding suggests ways to identify new metabolic pathways affected by schistosomiasis and also potential molecular targets to treat associated morbidities.

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Section: Discussionsupporting

confidence: 68%

Human Plasma Lipid Modulation in Schistosomiasis Mansoni Depends on Apolipoprotein E Polymorphism

et al. 2014

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“…Acquired chromosomal aberrations associated with retrotransposon propagation at this location predispose to sporadic AAA. In addition, genes located in this chromosomal region have been implicated in the development of systemic sclerosis and hepatic fibrosis (HF) [ 62 , 63 ]. Functional single nucleotide polymorphisms (SNPs, rs6918698) implicated CCN2 as a major actor in severe HF in schistosome-infected Chinese, Sudanese, and Brazilian subjects [ 64 ].…”

Section: Introductionmentioning

confidence: 99%

Eyeing the Cyr61/CTGF/NOV (CCN) group of genes in development and diseases: highlights of their structural likenesses and functional dissimilarities

2015

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“CCN” is an acronym referring to the first letter of each of the first three members of this original group of mammalian functionally and phylogenetically distinct extracellular matrix (ECM) proteins [i.e., cysteine-rich 61 (CYR61), connective tissue growth factor (CTGF), and nephroblastoma-overexpressed (NOV)]. Although “CCN” genes are unlikely to have arisen from a common ancestral gene, their encoded proteins share multimodular structures in which most cysteine residues are strictly conserved in their positions within several structural motifs. The CCN genes can be subdivided into members developmentally indispensable for embryonic viability (e.g., CCN1, 2 and 5), each assuming unique tissue-specific functions, and members not essential for embryonic development (e.g., CCN3, 4 and 6), probably due to a balance of functional redundancy and specialization during evolution. The temporo-spatial regulation of the CCN genes and the structural information contained within the sequences of their encoded proteins reflect diversity in their context and tissue-specific functions. Genetic association studies and experimental anomalies, replicated in various animal models, have shown that altered CCN gene structure or expression is associated with “injury” stimuli—whether mechanical (e.g., trauma, shear stress) or chemical (e.g., ischemia, hyperglycemia, hyperlipidemia, inflammation). Consequently, increased organ-specific susceptibility to structural damages ensues. These data underscore the critical functions of CCN proteins in the dynamics of tissue repair and regeneration and in the compensatory responses preceding organ failure. A better understanding of the regulation and mode of action of each CCN member will be useful in developing specific gain- or loss-of-function strategies for therapeutic purposes.

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“…New anti‐ Schistosoma drugs and inhibitors of fibrosis have been investigated, but their routine use is still far from daily practice. However, this prediction might change rapidly with the elucidation of gene regulation involved in disease progression, thereby opening new horizons on disease staging, therapy, and clinical management of Schistosoma liver disease . Moreover, the presence of comorbidities such as coinfections with viral hepatitis, the use of immunosuppressive drugs, and organ transplantation pose new challenges.…”

Section: Clinical Managementmentioning

confidence: 99%

Schistosomiasis: Clinical management of liver disease

Cavalcanti

Araujo-Neto

Peralta

2015

Clinical Liver Disease

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Infection with hepatitis C virus (HCV) has become the most important public health problem in Egypt. In Egypt, viral hepatitis along with infection with Schistosoma mansoni is the major cause of chronic liver disease and liver cirrhosis. Although HCV infection is highly prevalent in Egypt, very little information is available on the distribution of the different genotypes of HCV. Our aims in this study were first to determine the prevalence of viral and parasite infections in patients with chronic liver disease and then to assess the distribution of HCV genotypes in these patients. In the present study, 151 individuals (50 with chronic liver disease, 51 with chronic diseases of organs other than the liver, and 50 apparently healthy persons) were investigated. The last 2 groups served as control groups. These individuals were subjected to routine liver function tests and detection of serum antibodies to bilharziasis, hepatitis B surface antigen (HBsAg), and HCV. Furthermore, the presence of hepatitis G virus (HGV) and HCV in the serum samples were tested for by a reverse transcription polymerase chain reaction (RT-PCR). Prevalence of different genotypes of HCV in patients positive for HCV were determined by RT-PCR using type-specific primers. Results of the study revealed that 84, 74, 12, and 20% of patients with chronic liver disease were positive for Schistosoma mansoni, HCV, HBsAg, and HGV, respectively, as compared to 51, 43.1, 2, and 4% of patients with other chronic diseases and 22, 6, 0, and 0% of apparently healthy individuals. One hundred percent of patients with chronic liver disease, 72.5% of those with other diseases, and 26% of normal controls were shown to have at least one of the studied infectious agents. Two or more of the agents were highly coincident in patients with chronic liver disease. In Egypt, HCV genotype 4a is highly prevalent, where it contributed 85% of the tested samples in comparison to 10, 2.5, and 2.5% for subtypes 1b, 2a, and 3a, respectively. In conclusion, these results suggest that in Egypt, HCV along with schistosomal parasite infection is the major risk factor for chronic liver disease. In most Egyptian patients, HCV genotype 4 is highly prevalent. Hepatitis C virus (HCV) has been identified as the major causative agent of posttransfusion and sporadic community-acquired non-A, non-B hepatitis (NANBH). 1,2 Hepatitis C virus is a single-stranded RNA virus closely related to pes-tiviruses and flaviviruses. The viral RNA has 2 short non-translational regions at the 5 and 3 ends enclosing a single large open reading frame. Individual proteins, the core (C), envelope (E1 and E2), and nonstructural proteins (NS1-NS5) 3,4 are cleaved from the polyprotein by host and viral protease. Hepatitis C virus is highly prevalent in Egypt, where its antibodies were detected in 10-30% of the Egyp-tian population. 5-8 Recently, HCV infection was concluded to be the main cause of chronic liver disease in Egypt, where this infection is largely associated with schistosomiasis (Gandin C and others, ...

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Genetic analysis of human predisposition to hepatosplenic disease caused by schistosomes reveals the crucial role of connective tissue growth factor in rapid progression to severe hepatic fibrosis

Cited by 16 publications

References 52 publications

Human Plasma Lipid Modulation in Schistosomiasis Mansoni Depends on Apolipoprotein E Polymorphism

Human Plasma Lipid Modulation in Schistosomiasis Mansoni Depends on Apolipoprotein E Polymorphism

Eyeing the Cyr61/CTGF/NOV (CCN) group of genes in development and diseases: highlights of their structural likenesses and functional dissimilarities

Schistosomiasis: Clinical management of liver disease

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