Prospective analysis suggests susceptibility genes for deficiencies of IgAand several other immunoglobulins on the [HLA-B8, SCO1, DR3] conserved extended haplotype

The extended major histocompatibility complex (MMC) haplotype [HLA-B8, SC01 , DR3] is increased in frequency among patients with immunoglobulin (Ig)A d eficiency and common variable immunodeficiency. Because the genomic region from HLA-B to HLA-DR/DQ is virtually the same on ail instances of the haplo type in the general population, we reasoned that all independent instances of [HLA-B8, SC01, DR3] carry MHC susceptibility genes for these disorders. To define immunoglobulin deficiencies determined by genes on this haplotype and their mode of expression and penetrance, serum immunoglobulin class an d IgG subclass concentrations were determined prospectively in homozygotes and heterozygotes of this haplotype and in Caucasian controls. Prevalence o f individual immunoglobulin deficiencies in persons with [HLA-B8, SC01, DR3 ] ranged from 13% to 37%, significantly higher than rates in non-carriers o r general controls. We found significantly increased frequencies of IgA and IgG4 deficiency only homozygotes (13.3% and 30%, respectively) compared wi th heterozygotes (1.7% and 3.4%) or non-carriers (1.6% each), suggesting re cessive expression. In contrast, IgD and IgG3 deficiencies were significant ly more common in both homozygotes (36.7% and 30%) and heterozygotes (20.3% and 17.5%) compared with controls (4.9% and 3.4%), suggesting dominant inh eritance. These results indicate multiple distinct susceptibility genes, so me recessive and others dominant, fur deficiency of IgA, IgD, IgG3 or IgG4 (but not for IgE, IgG1, IgG2 or IgM) on [HLA-B8, SC01, DR3]. These observat ions may also help to explain the observed associations of [HLA-B8, SC01, D R3] with both IgA deficiency and common variable immunodeficiency and the c ommon occurrence of IgG subclass deficiencies in some patients with IgA def iciency.