Determination of candidate genes for Schistosomal fibrosis

The specific aims of this study are to characterize genetic patterns associated with schistosome-induced hepatic fibrosis and to link the development of hepatic fibrosis to polymorphic markers located near potential disease susceptibility genes. Approximately 70% of those age>11 in the community of Shamarka, in the Nile Delta were surveyed [n=2,038] for parasites and ultrasound evidence of fibrosis using the latest WHO criteria. The potential role of eleven regions containing genes that could be involved in the control of severe hepatic fibrosis was investigated by linkage analysis with the polymorphic markers. Segregation analysis was performed by the regressive logistic model. Tow - point LOD scores for various values of the recombination fraction [theta] were computed by means of the LINKAGE package and by the use of the major-gene model obtained from segregation analysis. A candidate gene search was carried out on 90 affected sibling pairs from 40 pedigrees in this community. From 2-4 single nucleotide polymorphisms [SNPs] were used per locus. Using the most conservative correction for multiple comparisons and the WHO ultrasound pattern, he INFGRI locus demonstrated a significant linkage for 1 of 4 SNPs [p=0.0014298]. The analysis further suggests that TGF beta 1 and the IL 13-4 region might also contribute to the development of fibrosis, but their scores did not reach significance after correction. The present work shows that severe fibrosis in subjects infected by S. mansoni is determined by a major locus that maps close to the IFN-gamma R1 gene. This finding opens that way to both the identification of the gene and the evaluation of its role in the determination of abnormal fibrosis of other etiological origins. Finally, our results will stimulate new strategies in drug and vaccine development