RESUMEN
Sclerosteosis is a rare autosomal recessive condition characterized by increased bone density. Mutations in SOST gene coding for sclerostin are linked to sclerosteosis. Two Egyptian brothers with sclerosteosis and their apparently normal consanguineous parents were included in this study. Clinical evaluation and genomic sequencing of the SOST gene were performed followed by in silico analysis of the resulting variation. A novel homozygous frameshift mutation in the SOST gene, characterized as one nucleotide cytosine insertion that led to premature stop codon and loss of functional sclerostin, was identified in the two affected brothers. Their parents were heterozygous for the same mutation. To our knowledge this is the first Egyptian study of sclerosteosis and SOST gene causing mutation.
Asunto(s)
Proteínas Morfogenéticas Óseas/genética , Marcadores Genéticos/genética , Hiperostosis/genética , Mutación/genética , Sindactilia/genética , Proteínas Adaptadoras Transductoras de Señales , Adolescente , Adulto , Secuencia de Aminoácidos , Secuencia de Bases , Proteínas Morfogenéticas Óseas/química , Niño , Análisis Mutacional de ADN , Egipto , Familia , Femenino , Humanos , Hiperostosis/diagnóstico por imagen , Masculino , Modelos Genéticos , Datos de Secuencia Molecular , Proteínas Mutantes/química , Proteínas Mutantes/metabolismo , Linaje , Radiografía , Sindactilia/diagnóstico por imagenRESUMEN
The polymorphism of interleukin 28B (IL28B) rs12979860 is associated with spontaneous and treatment-induced clearance in hepatitis C virus (HCV) genotype 4 (G4). However, there is no information on its interaction with gender, moreover its association with intrahepatic inflammation in North Africans is not studied and its association with fibrosis in North Africans (especially Egyptians) is controversial. This study aims to explore the association between the minor allele of the IL28B rs12979860 polymorphism with gender, fibrosis and necroinflammation in Egyptian G4 HCV patients. IL28B rs12979860 was genotyped in 224 individuals, including 100 healthy controls and 124 consecutive patients with chronic HCV. Results showed (1) IL28B rs12979860 minor alleles associated with susceptibity to chronic HCV mainly in men not women, (2) no association between IL28B rs12979860 with fibrosis and necroinflammation activity, (3) the IL28B rs12979860 TT genotype associated with severe fibrosis in women only and with the necroinflammation activity in men using a recessive model. In conclusion, the IL28B rs12979860 polymorphism is not associated with fibrosis and liver inflammation in Egyptian HCV G4. Nonetheless, the TT genotype of IL28B rs12979860 polymorphism affects the natural history of each gender independently.
Asunto(s)
Fibrosis/genética , Hepacivirus/genética , Interleucinas/genética , Hepatopatías/genética , Polimorfismo Genético/genética , Caracteres Sexuales , Adulto , Egipto , Femenino , Fibrosis/sangre , Genotipo , Humanos , Inflamación/genética , Interferones , Interleucinas/sangre , Hepatopatías/metabolismo , Hepatopatías/virología , MasculinoRESUMEN
INTRODUCTION: Hepatitis C virus (HCV) infection affects almost 3% of the world's population with the highest prevalence in Egypt (15%). The standard therapy; pegylated interferon (PEG-IFN) and ribavirin, is effective in only 60% of Egyptian patients; moreover it is costly, prolonged, and has severe side effects, so prediction of response is essential to reduce burden of unfavorable treatment. Several viral and host factors have been proved to affect response to the treatment PEG-IFN and ribavirin; the strongest of them is polymorphisms near IL28B; nonetheless, nonresponse in patients with favorable IL28B is still unexplained, which implies the importance of studying other immunological factors that may correlate with response. Interleukin 12 (IL-12) is one of the most important proinflammatory cytokine presented with the initiation of immune response, determining Th1 and Th2 differentiation. A functional single nucleotide polymorphism (A/C) at the 3' untranslated region (3'UTR) at position 1188 (NCBI SNP database no 3212227) was reported to be associated with responding more efficiently to antiviral combination therapy in HCV genotype 1 infected patients. The present study aims to evaluate association between this polymorphism with fibrosis stages, necroinflammation activity, response to the combined therapy, and gender in Egyptian HCV genotype 4. MATERIAL AND METHODS: A total of 133 Egyptian chronic HCV (CHCV) patients were treated with IFN/RBV and were followed up. IL12B 1188 A/C genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PRC-RFLP) analysis. RESULTS: A nonsignificant trend for higher sustained virological response (SVR) was observed in patients homozygote for IL12B 1188 A/C SNP CC genotype (69% SVR versus 30.8% NR) only but not in AC and AA genotypes. No association was detected between IL12B 1188 A/C polymorphism and less severe fibrosis or less liver activity. By stratification of response according to gender genotype, a significant difference in response between males and females was seen among AA genotype carriers only due to high number of non responder females. CONCLUSION: IL12B CC genotype appears to have some influence on SVR achievement but not on severe fibrosis and severe necroinflamation activity. Females carrying A/A genotype of IL12B 1188 A/C SNP achieve less SVR than those carrying AC and CC genotypes.
Asunto(s)
Genotipo , Hepatitis C/genética , Subunidad p40 de la Interleucina-12/genética , Hígado/patología , Polimorfismo de Nucleótido Simple , Adulto , Egipto , Femenino , Fibrosis/diagnóstico , Fibrosis/tratamiento farmacológico , Fibrosis/genética , Fibrosis/patología , Estudios de Asociación Genética , Hepatitis C/diagnóstico , Hepatitis C/tratamiento farmacológico , Hepatitis C/patología , Humanos , Interferones/uso terapéutico , Masculino , Persona de Mediana Edad , Polimorfismo de Longitud del Fragmento de Restricción , Ribavirina/uso terapéutico , Factores Sexuales , Resultado del TratamientoRESUMEN
Hepatitis C virus (HCV) infection is a major health problem worldwide. Egypt is the country with the highest HCV infection epidemic in the world. Interleukin (IL)-12 is a cytokine that has been shown to have a potent role as an antiviral cytokine. IL-12 is a heterodimer of the polypeptides p35 and p40. IL-12 B, the gene encoding IL-12 p40, is polymorphic, and a functional single-nucleotide polymorphism (SNP) of the 3'-untranslated region at position rs3212227 was associated with apparent resistance to HCV. The genotype distribution of this polymorphism differs by race. This study is sought to identify the genotype distribution of the IL-12 SNP rs3212227 polymorphism in Egyptians and to assess its role in susceptibility to chronic HCV infection alone or in a sex-dependent way. The study included 238 subjects: 100 healthy controls and 138 patients with HCV infection. The IL-12 SNP rs3212227 was genotyped by the polymerase chain reaction-restriction fragment length polymorphism method (PCR-RFLP). Results showed a genotype frequency of 46%, 39%, and 15% for AA, AC, and CC IL-12 genotypes, respectively. No significant result (P=0.5) was shown in the differential distribution of the IL-12 SNP genotypes between controls and patients with HCV infection. Nonetheless, this difference in the IL-12 genotype distribution was significant (0.005) when it was stratified according to sex; moreover, the C allele distribution in men and women differed with a statistically high significance (P=0.0001) in controls versus HCV patients. In conclusion, the IL-12 SNP rs3212227 polymorphism confers a susceptibility to HCV infection in a sex-dependent way in Egyptians.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Hepatitis C/genética , Subunidad p40 de la Interleucina-12/genética , Polimorfismo de Nucleótido Simple , Adulto , Anticuerpos Antivirales/inmunología , Egipto , Ensayo de Inmunoadsorción Enzimática , Femenino , Frecuencia de los Genes , Genotipo , Hepacivirus/inmunología , Hepacivirus/fisiología , Hepatitis C/virología , Interacciones Huésped-Patógeno , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Factores SexualesRESUMEN
Background. Occult hepatitis C virus infection (OCI) was identified as a new form of Hepatitis C virus (HCV), characterized by undetectable HCV antibodies and HCV RNA in serum, while HCV RNA is detectable in liver and peripheral blood cells only. Aim. The aim of this study was to investigate the occurrence of OCI in Egyptian patients with lymphoproliferative disorders (LPDs) and to compare its prevalence with that of HCV in those patients. Subjects and Methods. The current study included 100 subjects, 50 of them were newly diagnosed cases having different lymphoproliferative disorders (patients group), and 50 were apparently healthy volunteers (controls group). HCV antibodies were detected by ELISA, HCV RNA was detected in serum and peripheral blood mononuclear cells (PBMCs) by reverse transcription polymerase chain reaction(RT-PCR), and HCV genotype was detected by INNO-LiPA. Results. OCI was detected in 20% of patients group, compared to only 4% OCI in controls group. HCV was detected in 26% of patients group with a slightly higher prevalence. There was a male predominance in both HCV and OCI. All HCV positive patients were genotype 4. Conclusion. Our data revealed occurrence of occult HCV infection in Egyptian LPD patients at a prevalence of 20% compared to 26% of HCV.