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

Concha, Emilio G. de la; Fernández‐Arquero, Miguel; Martínez, Alfonso; Vidal, Francisco; Vigil, Patricia; Conejero, Laura; García‐Rodriguez, M. C.; Fontán, G

doi:10.1046/j.1365-2249.1999.00926.x

Cited by 30 publications

(17 citation statements)

References 24 publications

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“…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.…”

Section: Role Of Igad1 Homozygosity In Susceptibility To Igad/cvidsupporting

confidence: 73%

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

Vořechovský

Cullen

Carrington

et al. 2000

The Journal of Immunology

114

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To limit the region containing a mutation predisposing to selective IgA deficiency (IgAD) and common variable immunodeficiency (CVID), 554 informative members of 101 multiple-case families were haplotyped at the IGAD1 candidate locus in the MHC. Microsatellite markers were placed onto the physical map of IGAD1 to establish their order and permit rapid haplotype analyses. Linkage analysis of this extended family set provided additional support for a strong susceptibility locus at IGAD1 with a maximum multipoint nonparametric linkage score in excess of 3. Although the transmission of maternal IGAD1 haplotypes from unaffected heterozygous parents to the affected offspring was in excess, this was not apparent in multiple-case families with a predominance of affected mothers, suggesting that this parental bias is influenced by the affection status of transmitting parents and supporting a maternal effect in disease susceptibility. Of 110 haplotypes shared by 258 affected family members, a single haplotype (H1) was found in 44 pairs of affected relatives, accounting for the majority of the IGAD1 contribution to the development of IgAD/CVID in our families. The H1 allelic variability was higher in the telomeric part of the class III region than in the distal part of the class II region in both single- and multiple-case families. Incomplete H1 haplotypes had most variant alleles in the telomeric part of the analyzed region in homozygous IgAD/CVID patients, whereas this was not observed in unaffected homozygotes. These data suggest that a telomeric part of the class II region or centromeric part of the class III region is the most likely location of IGAD1. 1 This study was supported by the Swedish and British Medical Research Councils, the Swedish Strategic Research Foundation, the Primary Immunodeficiency Association of the United Kingdom MSMT VS96097, the Karolinska Institute, and federal funds from the National Cancer Institute, National Institutes of Health, under Contract NO1-CO-56000. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. 2 Address correspondence and reprint requests to Dr. Igor Vořechovský, Department of Biosciences at NOVUM, Karolinska Institute, CBT Hälsovägen 7, SE-14157 Huddinge, Sweden. E-mail address: igvosmtp.biosci.ki.se Abbreviations used in this paper: IgAD, selective IgA deficiency; CVID, common variable immunodeficiency; TDT, transmission disequilibrium test; NPL, nonparametric linkage; PCR-SSP, PCR using sequence-specific oligonucleotide primers.

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Section: Role Of Igad1 Homozygosity In Susceptibility To Igad/cvidsupporting

confidence: 73%

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

Vořechovský

Cullen

Carrington

et al. 2000

The Journal of Immunology

114

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“…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).…”

Section: Homozygosity At Hla-dq/drsupporting

confidence: 64%

“…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.…”

Section: Homozygosity At Hla-dq/drmentioning

confidence: 99%

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

Královičová

Hammarström

Plebani

et al. 2003

The Journal of Immunology

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Selective IgA deficiency (IgAD) and common variable immunodeficiency (CVID) are the most common primary immunodeficiencies in humans. A high degree of familial clustering, marked differences in the population prevalence among ethnic groups, association of IgAD and CVID in families, and a predominant inheritance pattern in multiple-case pedigrees have suggested a strong, shared genetic predisposition. Previous genetic linkage, case-control, and family-based association studies mapped an IgAD/CVID susceptibility locus, designated IGAD1, to the MHC, but its precise location within the MHC has been controversial. We have analyzed a sample of 101 multiple- and 110 single-case families using 36 markers at the IGAD1 candidate region and mapped homozygous stretches across the MHC shared by affected family members. Haplotype analysis, linkage disequilibrium, and homozygosity mapping indicated that HLA-DQ/DR is the major IGAD1 locus, strongly suggesting the autoimmune pathogenesis of IgAD/CVID. This is supported by the highest excess of allelic sharing at 6p in the genome-wide linkage analysis of 101 IgAD/CVID families using 383 marker loci, by previously reported restrictions of the T cell repertoires in CVID, the presence of autoantibodies, impaired T cell activation, and a dysregulation of a number of genes in the targeted immune system. IgAD/CVID may thus provide a useful model for the study of pathogenesis and novel therapeutic strategies in autoimmune diseases.

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“…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.…”

Section: Discussionmentioning

confidence: 91%

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

et al. 2000

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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.

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

Cited by 30 publications

References 24 publications

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

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

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

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

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