Complotypes, extended haplotypes, male segregation distortion, and disease markers

Abstract

From our studies in Caucasian families of HLA, complement, and glyoxalase alleles have developed the concepts of the complotype and the extended haplotype. complotypes are clusters of the four genes for complement proteins encoded within the MHC designated (in arbitrary order) by their BF, C2, C4A, and C4B alleles. They are inherited in families and occur in populations as functionally single genetic units and exhibit linkage disequilibrium with HLA-B and HLA-DR alleles which are complotype, rather than complement gene allele, specific. In Caucasians, there are 10-12 common sets of HLA-B, DR, complotype sets that show significant linkage disequilibrium. These haplotypes constitute 25-30% of all MHC haplotypes in Caucasians. Because there is evidence for relative fixity of alleles on these chromosomes to an unknown extent beyond the HLA-B-DR interval, they have been called extended MHC haplotypes. It appears likely that it is these extended haplotypes that provide most of the known linkage disequilibrium pairs previously reported for MHC alleles as well as many of the known MHC allele-disease associations. The most common extended haplotype [HLA-B8, DR3, SC01], when it carries GLO2, is increased in type I diabetes mellitus and probably a number of other diseases, including gluten-sensitive enteropathy and membranoproliferative glomerulonephritis. In the families with these disorders studied by us, this haplotype exhibits male segregation distortion, a feature displayed by t-mutants found in wild mouse populations. This feature constitutes an important selective advantage for the chromosome and may contribute to the accumulation of susceptibility mutations for a variety of diseases.(ABSTRACT TRUNCATED AT 250 WORDS)