Incomplete penetrance of MHC susceptibility genes: prospective analysis ofpolygenic MHC-determined traits

We propose an approach to understanding incomplete penetrance of disease su sceptibility genes as a method of studying the underlying mechanisms of pol ygenic diseases. Incomplete penetrance is the failure of genetically suscep tible individuals to exhibit a trait. We define as baseline penetrance that which occurs in genetically identical (monozygotic) twins of an index subj ect with a major histocompatibility complex (MHC)-associated disease or tra it. We consider two mechanisms for incomplete baseline penetrance: an extri nsic (environmental) trigger and an intrinsic stochastic, gene-associated p rocess. The latter can be detected fur dominant expression because suscepti bility genes in homozygotes (with their two intrinsic triggers) will be up to twice as frequently penetrant as those in heterozygotes, The extent of M HC and non-MHC gene contribution determines differences between baseline pe netrance and apparent penetrance in MHC-identical sib pairs, sib pairs in g eneral and MHC-identical unrelated individuals. Inheritance patterns in fam ilies do not reveal modes of inheritance of incompletely penetrant polygeni c MHC-determined traits. A method is proposed to study such traits prospect ively in persons presumed to be homozygous, heterozygous or non-carrying fo r susceptibility genes by determining trait expression in homozygotes, hete rozygotes or non-carriers of trait-associated conserved extended MHC haplot ypes. The method provides direct estimates of apparent penetrance rates, mo des of genetic determination, and, if the trait is dominant, the origin of penetrance. When applied to dominant MHC susceptibility gene-determined imm unoglobulin deficiencies in two populations, the ratios of affected haploty pe homozygotes to heterozygotes near 2.0 were consistent with an intrinsic mechanism for baseline penetrance acting on the MHC susceptibility genes.