To understand the genetic predisposition to selective immunoglobulin A deficiency (IgAD), we performed a genome-wide association study in 430 affected individuals (cases) from Sweden and Iceland and 1,090 ethnically matched controls, and we performed replication studies in two independent European cohorts. In addition to the known association of HLA with IgAD, we identified association with a nonsynonymous variant in IFIH1 (rs1990760G>A, P = 7.3 x 10(-10)) which was previously associated with type 1 diabetes and systemic lupus erythematosus. Variants in CLEC16A, another known autoimmunity locus, showed suggestive evidence for association (rs6498142C>G, P = 1.8 x 10(-7)), and 29 additional loci were identified with P < 5 x 10(-5). A survey in IgAD of 118 validated non-HLA autoimmunity loci indicated a significant enrichment for association with autoimmunity loci as compared to non-autoimmunity loci (P = 9.0 x 10(-4)) or random SNPs across the genome (P < 0.0001). These findings support the hypothesis that autoimmune mechanisms may contribute to the pathogenesis of IgAD.
Selective IgA deficiency (SIgAD) is the most common primary immunodeficiency in Caucasians with a prevalence of 1/600 and is generally considered a mild disorder. In this study, the clinical status of 32 adults with SIgAD was investigated and compared to 63 age- and gender matched controls, randomly selected from a population database. The SIgAD individuals reported significantly more often contracting various upper and lower respiratory infections, with 8 (25.0 %) having been diagnosed with ≥1 pneumonia in the preceding two years, compared to one (1.6 %) control (p < 0.001). Furthermore, the SIgAD individuals were found to have increased proneness to infections and increased prevalence of allergic diseases and autoimmunity, with a total of 84.4 % being affected by any of these diseases, compared to 47.6 % of the controls (p < 0.01). This study challenges the common statement of SIgAD being a mild form of immunodeficiency. It also highlights the importance of using matched controls in PID clinical research to better detect clinically important manifestations.
Primary immunodeficiency diseases (PID) are a genetically heterogenous group of >150 disorders that affect distinct components of the innate and adaptive immune system and are often associated with autoimmune diseases. We describe PID affecting T‐regulatory cells, complement and B cells or their products and discuss the possibility of a cause–effect relationship. The high concordance of T‐regulatory cell defects to organ‐specific autoimmune disease implies an obligatory role of these cells in maintaining tolerance to epithelial and endocrine tissues; the absence of central nervous system involvement may reflect immunological privilege. Congenital defects in C1q, C1r/s and C4 are strongly associated with systemic lupus erythematosus (SLE), and this pattern along with laboratory evidence suggests a major importance of classical pathway activity in safe elimination of immune complexes and prevention of immune complex disease (ICD). It is debatable whether this ICD is to be regarded as an autoimmune disease (resulting from a breakdown of immunological ignorance to antigens that are normally hidden), as autoantibodies may be absent, and tissue damage because of deposition of immune complexes could account for all of the pathology observed. Evidence for a causative link between primary antibody deficiencies and autoimmune disease is much less compelling and may in fact involve a common genetic background. However, arguments have also been made in favour of the notion that an intense antigen load as a result of recurrent or persistent infections may affect either tolerance or ignorance, e.g. by molecular mimicry or the presence of superantigens. Similar immunological mechanisms might account for the vast majority of autoimmune diseases.
Selective IgA deficiency (IgAD; serum IgA<0.07 g/l) is the most common form of human primary immune deficiency, affecting approximately 1∶600 individuals in populations of Northern European ancestry. The polygenic nature of IgAD is underscored by the recent identification of several new risk genes in a genome-wide association study. Among the characterized susceptibility loci, the association with specific HLA haplotypes represents the major genetic risk factor for IgAD. Despite the robust association, the nature and location of the causal variants in the HLA region remains unknown. To better characterize the association signal in this region, we performed a high-density SNP mapping of the HLA locus and imputed the genotypes of common HLA-B, -DRB1, and -DQB1 alleles in a combined sample of 772 IgAD patients and 1,976 matched controls from 3 independent European populations. We confirmed the complex nature of the association with the HLA locus, which is the result of multiple effects spanning the entire HLA region. The primary association signal mapped to the HLA-DQB1*02 allele in the HLA Class II region (combined P = 7.69×10−57; OR = 2.80) resulting from the combined independent effects of the HLA-B*0801-DRB1*0301-DQB1*02 and -DRB1*0701-DQB1*02 haplotypes, while additional secondary signals were associated with the DRB1*0102 (combined P = 5.86×10−17; OR = 4.28) and the DRB1*1501 (combined P = 2.24×10−35; OR = 0.13) alleles. Despite the strong population-specific frequencies of HLA alleles, we found a remarkable conservation of these effects regardless of the ethnic background, which supports the use of large multi-ethnic populations to characterize shared genetic association signals in the HLA region. We also provide evidence for the location of association signals within the specific extended haplotypes, which will guide future sequencing studies aimed at characterizing the precise functional variants contributing to disease pathogenesis.
The study highlights the importance of identifying and thoroughly evaluating, educating and following up individuals with SIgAD, as their HRQL may be negatively affected due to health problems possible to prevent and treat.
IgAD predisposes to oral mucosal infections but does not influence periodontal or dental health. This is the first controlled study to include detailed clinical history and investigations, together with full oral and dental examination, in adults with IgAD.
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