The overall objective of the planned research is the further definition of genetic control of proteins in the human complement system. In particular, subtypes of common C4A and C4B alleles will be sought in order to provide more informative complotypes for the identification of extended major histocompatibility complex haplotypes as markers for disease susceptibility, for immune response and immune suppression genes and for previously isolated human populations. The subtypes of common C4A and C4B alleles will be identified by isoelectric focusing of desialated whole molecules and by apparent size polymorphisms in C4 Beta and Gamma chains detected by sodium dodecyl sulfate electrophoresis. Any such variation detected will be studied in families to provide allele frequencies, evidence for inheritance and relationship to other major histocompatibility complex markers, including restriction fragment length polymorphisms in genomic DNA. Other studies will define genetic polymorphism in human Clq and Cls. For Clq, charge variation in A, B and C subunits will be investigated and localized to collagen-like stalk and stem or to globular head fragments. For Cls, the variation will be localized to one chain or the other of Cls, inheritance will be shown in family studies and population allele frequencies will be determined. Linkage relationships will be studied among possible loci for the subunits of Cq, between these and that for Cls, and between the Cl loci and other complement loci. From these studies, we hope to obtain new insights into genetic control of C4, Clq and Cls and into the evolution of the complement system in man.
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