Prospective analysis suggests susceptibility genes for deficiencies of IgA and several other immunoglobulins on the [HLA‐B8, SC01, DR3] conserved extended haplotype

Abstract

The extended major histocompatibility complex (MHC) haplotype [HLA-B8, SC01, DR3] is increased in frequency among patients with immunoglobulin (Ig)A deficiency and common variable immunodeficiency. Because the genomic region from HLA-B to HLA-DR/DQ is virtually the same on all instances of the haplotype 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 and IgG subclass concentrations were determined prospectively in homozygotes and heterozygotes of this haplotype and in Caucasian controls. Prevalence of individual immunoglobulin deficiencies in persons with [HLA-B8, SC01, DR3] ranged from 13% to 37%, significantly higher than rates in non-carriers or general controls. We found significantly increased frequencies of IgA and IgG4 deficiency only in homozygotes (13.3% and 30%, respectively) compared with heterozygotes (1.7% and 3.4%) or non-carriers (1.6% each), suggesting recessive expression. In contrast, IgD and IgG3 deficiencies were significantly 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 inheritance. These results indicate multiple distinct susceptibility genes, some recessive and others dominant, for deficiency of IgA, IgD, IgG3 or IgG4 (but not for IgE, IgG1, IgG2 or IgM) on [HLA-B8, SC01, DR3]. These observations may also help to explain the observed associations of [HLA-B8, SC01, DR3] with both IgA deficiency and common variable immunodeficiency and the common occurrence of IgG subclass deficiencies in some patients with IgA deficiency.

Incomplete penetrance of susceptibility genes for MHC-determined immunoglobulin deficiencies in monozygotic twins discordant for type 1 diabetes

“…We had earlier explored the nature and extent of apparent penetrance of Igds through the study of unrelated individuals who were homozygous, heterozygous or non-carrying for CEHs [5][6][7] known or suspected to carry susceptibility genes for MHC-determined Igds such as IgAd [16], IgDd [22], IgG3d and IgG4d. CEHs are ≥ 1 Mb stretches of fixed genomic DNA defined by their HLA-B, complotype, and HLA-DR alleles [23].…”

“…It is elevated in frequency in patients with a variety of autoimmune diseases, including T1D [24], GSE [26], myasthenia gravis [27] and systemic lupus erythematosus [28]. It is also associated with IgAd [16], IgDd [22], IgG3d [5] and IgG4d [5].…”

“…We previously found incomplete penetrance for certain MHC-determined immunoglobulin deficiencies (Igds) [5][6][7]. Thus, incomplete penetrance could be a general intrinsic property of some MHC genes.…”

MHC Susceptibility Genes to IgA Deficiency Are Located in Different Regions on Different HLA Haplotypes

“…In recent years, despite the development of high-density genetic maps and large kindred studies, the point has not been completely settled; although the telomeric part of the MHC class III region is usually favored (13,15), a report points to the telomeric part of the MHC class II region (19). Most studies published in recent years (13,14,19,20) have focused on IgAD patients bearing the B8-DR3 haplotype, because this is the most common haplotype associated with IgAD in Caucasians. However, in Spanish white IgAD patients, HLA-DR1 and HLA-DR7 are even more frequent than HLA-DR3 (21), reflecting the distribution of HLA-DR alleles and extended haplotypes in southern Europe, where HLA-DRB1*0102 (carried on the B14-DR1 haplotype) and DR7 are more frequent than in northern Europe and the U.S. (22).…”

Epistatic effects occurring among susceptibility and protective MHC genes in IgA deficiency

“…Although for each individual genotype, 95% confidence interval was very large and no statistically significant results could be obtained, the data were rather impressive and added to that of their sum shown in the previous paragraph (P ¼ 0.00001; OR ¼ 3.94) point to a dose-related effect in most instances. It has been recently reported, 17 studying individuals positive for the HLA-DR3/B8 haplotype, that increased frequencies of IgAD are only found in homozygotes for this conserved, extended haplotype and have suggested a recessive inheritance with a low penetrance. Although we have observed that all three susceptibility MHC haplotypes (those carrying either DRB1 * 0102, DR7, or DR3-TNFa2b3) are sufficient for conferring susceptibility to IgAD, we also see that they are greatly influenced by genes on the other MHC haplotype, and the strong dosage effect of the HLA-DR3/B8 haplotype has to be acknowledged.…”