Zen and David to present at Student Seminar Thursday (17.Dec) at noon in 2166 MERF
Background for Zen’s talk
The Role of the Alternative Pathway of the Complement System in the Development of Dense Deposit Disease
Dense Deposit Disease (DDD) causes chronic renal dysfunction which progresses to end-stage renal disease in about half of patients within 10 years of diagnosis. Deficiency of and mutations in complement Factor H (CFH) are associated with the development of DDD, suggesting that dysregulation of the alternative pathway (AP) of the complement cascade is important in disease pathophysiology. Patients with DDD are studied to determine whether specific allele variants of the genes of the alternative pathway of the complement system segregate preferentially with the DDD. We have screened coding and intronic regions of genes of the complement system in 71 DDD patients and 268 controls using PCR, restriction digest and bidirectional sequencing. We are able to identify novel mutations, allele variants and haplotypes in several genes of the complement system which are associated with the DDD phenotype using Chi-square test of independence, Armitage trend test and Haplotype analysis. The best inheritance model has been determined for each polymorphism. Our results have shown that the best inheritance pattern for most polymorphisms is a dominant model. Since we have identified several genes associated with DDD, we have determined possible gene-gene interactions using Multifactorial Dimensionality Reduction, Focused Interaction Testing Framework and Conditional Logistic Regression. We have found a strong synergistic interaction between polymorphisms in CFH and C3. To ascertain if the associated allele variants have a functional impact in the complement activity of an individual, we have obtained 102 blood samples from a blood bank and measured AP complement activity in these samples. We then have genotyped CFH and C3 for these samples and determined association using Conditional Logistic Regression, Mann-Whitney Test and Kruskal-Wallis Test. We have found significant association of main effects and two-way interaction of CFH and C3 with AP complement activity. Our data imply that DDD is a complex genetic disease and that polymorphisms in the genes of the AP pathway contribute to level of complement activity and the pathogenesis of DDD.
Background for David’s talk