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

Abstract

HLA class I and II frequencies and haplotype frequencies were determined in 80 German immunoglobulin (Ig)A‐deficient individuals and 157 healthy controls with normal IgA levels using serological and DNA typing methods. For several alleles, significant associations were found, which could be explained mainly in the context of a positive association with three different extended haplotypes (HLA‐B*08:DRB1*0301: DQB1*0201, HLA‐B*14:DRB1*0102:DQB1*0501 and HLA‐B*44:DRB1*0701:DQB1*0202) and a negative association with a fourth haplotype (HLA‐B*07:DRB1*1501:DQB1*0602). Furthermore, for the first time this study reports a positive association of IgA deficiency with DPB1 alleles. Homozygosity rate for the gene loci DRB1 and DQB1 was increased in IgA deficiency. Further analysis suggested a different pattern of HLA associations depending on the degree of IgA deficiency and the gender of the IgA‐deficient individuals.

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.…”

Selective IgA Deficiency in Autoimmune Diseases

“…Homozygosity for the ancestral 8.1 haplotype increases the risk of development of the disease even further (10). Other haplotypes, including HLA-DR7, DQ2 and DR1, DQ5 are also associated with IgAD (11). In contrast, the DR15, DQ6 haplotype has been shown to confer an almost complete protection against the disorder (12)(13)(14).…”

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

“…Most studies support a polygenic inheritance with a susceptibility locus (designated IGAD1) in the MHC. Associations of IgAD were first described with HLA class I alleles, most consistently with A1 and B8 (2-4) but also with A28, B14 (5-7), and B44 (8,9). Subsequently, an association with the class II allele HLA-DR3 was repeatedly observed (4, 9 -14), in addition to associations with DR1 (7, 9 -11) and DR7 (6,9,10,12).…”

“…Associations of IgAD were first described with HLA class I alleles, most consistently with A1 and B8 (2-4) but also with A28, B14 (5-7), and B44 (8,9). Subsequently, an association with the class II allele HLA-DR3 was repeatedly observed (4, 9 -14), in addition to associations with DR1 (7, 9 -11) and DR7 (6,9,10,12). Some early studies already signaled that the association was with particular combinations of MHC alleles rather than with individual alleles per se (5,7) and that these combinations reflected extended, conserved, or "ancestral" haplotypes A1-B8-DR3, A28-B14-DR1, and B44-DR7 (7,8,11,15).…”