HLA class II homozygosity confers susceptibility to common variable immunodeficiency (CVID)

Abstract

SUMMARYMost cases of CVID occur sporadically, but familial cases do also occur and 15% of the patients with the disease have ®rst degree relatives with IgA de®ciency (IgAD). Our purpose was to study CVID association with HLA class II alleles and to ascertain whether this disease shares a common genetic background with IgAD in our population. Patients with CVID (n 42), were typed using gene ampli®cation and sequence-speci®c oligonucleotide probing for HLA-DRB1, DRB3, DQA1 and DQB1 loci and their typing compared with that of 96 IgAD and 334 healthy controls. We observed a positive association between non-Asp residues at position 57 of the HLA-DQb chain and CVID, although much weaker than in IgAD. Further, we found an association between CVID and homozygosity for genes encoding HLA class II molecules, especially HLA-DQ, not seen in IgAD. The data support the hypothesis that a restricted diversity of HLA class II molecules may contribute to susceptibility to CVID.

Fine Mapping ofIGAD1in IgA Deficiency and Common Variable Immunodeficiency: Identification and Characterization of Haplotypes Shared by Affected Members of 101 Multiple-Case Families

“…However, the number of H1 homozygotes including H1 variants was almost tripled in affected individuals, possibly suggesting a role in IgAD/CVID predisposition via a putative recessive defect. Although we were not able to type all family members for HLA specificities because of the costs incurred, these results appear to correspond to those of de la Concha et al (30), who reported an increased number of class II homozygotes among CVID patients. However, this increase may not be a primary contributor to the disease susceptibility due to a restricted diversity of class II molecules as proposed (30) but could reflect the presence of a genuine predisposing mutation in close proximity to the class II genes.…”

Fine-Scale Mapping at IGAD1 and Genome-Wide Genetic Linkage Analysis Implicate HLA-DQ/DR as a Major Susceptibility Locus in Selective IgA Deficiency and Common Variable Immunodeficiency

“…Of 26 homozygous probands, only a single case exhibited homozygosity in the telomeric part of the class III region and not in the HLA-DQ/DR region. The frequencies of unaffected homozygous individuals (7.7% for 4-STRs and 5.9% for 5-STRs) were comparable to ϳ6 -8% homozygosity observed in large numbers of population controls typed for HLA-DR or -DQ specificities (38,39).…”

“…Because previous association studies suggested an increase of homozygosity in affected individuals vs controls both for HLA-DQ/DR (38,39) and HLA STRs (21), we estimated the relative risk of IgAD/CVID conferred by homozygous stretches at adjacent STRs and examined which region was associated with the highest risk. We chose to test 4-and 5-STR sliding windows because the average probability of being homozygous by chance was sufficiently low (ϳ2 ϫ 10 Ϫ3 and 3 ϫ 10 Ϫ4 , respectively), minimizing random homozygosity at adjacent STRs.…”

HLA‐A, B, Cw and DRB1, DRB3/4/5, DQB1, DPB1 Frequencies in German Immunoglobulin A‐Deficient Individuals

“…Moreover, the homozygosity rate for HLA-DRB1 and -DQB1 was signi®cantly higher in the partial IgA de®ciency group than in the control group or in severe IgA de®ciency. Interestingly, in a previous study by De La Concha et al [20] an association between common variable immunode®ciency and homozygosity for genes encoding HLA class II molecules was observed, whereas 210 H. K. G. Machulla et al [21]. The haplotype HLA-B8:DR3 is characterized by certain immunological features, e.g.…”