Genetics of immunoglobulin a deficiency

Sammanfattning: Immunoglobulin A deficiency (IgAD) is the most common primary immunodeficiency in Caucasian populations. It is defined as a serum IgA level below 0.07 g/L with normal IgM and IgG levels in an individual older than four years of age. Approximately one-third of these patients present with recurrent respiratory and gastrointestinal tract infections, allergic disorders and autoimmune manifestations. High familial clustering and prevalence variation by ethnicity both suggest the existence of a strong genetic component of the disease. Traditionally, IgAD has been reported as permanent, and sub-normal IgA levels remain static and persist after 20 years of observation. However, a few cases of reversion have been observed. We thus investigated the frequency of reversal in children and more than one-fifth (>20%) of Swedish children who were diagnosed before 10 years of age, reversed their IgAD status. Our observation suggests that the diagnosis of IgAD should not be made before the early teens using a cutoff level of 0.07 g/L of IgA in serum. After suggesting improved diagnostic guidelines, we investigated the role of genetics in IgAD in a Swedish Twin cohort. Surprisingly, the prevalence of IgAD was found to be markedly increased in a twin cohort as compared with the normal Swedish adult population. Although the MHC is the main genetic factor associated with IgAD development, the MHC haplotypes were not the primary factor causing the differences observed. Nonetheless, risk-conveying MHC haplotypes including HLA-A'01, HLA-B'08 and HLA-DRB1'01 were found to be associated with significantly lower serum IgA concentration in the twin cohort. On the contrary, individuals who carried the protective HLA alleles B'07, DRB1'15 and DQB1'06 were found to have significantly higher mean IgA concentration. We then performed a comprehensive analysis within the MHC region in order to identify the potential susceptibility genes/loci within the MHC region. In our large-scale case-control study, we identified an independent MHC haplotype (HLA-DPB1'1301) in the class II region associated with IgAD. In addition, MHC recombination analysis suggested a region around 110 Kbp which may contain a portion of the ancestral block. However, verification using complete sequencing did not identify any differences. Nonetheless, identification of 4310 new variants from ancestral 8.1 haplotypes will provide valuable information for the investigation of other MHC associated diseases. We also identified novel genes/variants within the MHC class III region including AGER (rs1800625), RNF5 (rs3130349), BTNL2 (rs1980493) and HCG23 (rs3117097) that are associated with IgAD risk. Subsequently, we investigated the association of non-MHC genes using different MHC risk haplotypes as category factors. In total, 14 different genes/loci were identified as potentially associated with IgAD in individuals carrying different MHC risk alleles, including one from HLA-B'0801-DRB1'0301-DQB1'0201 (ancestral haplotype), three from the HLA-DRB1'0701-DQB1'0202 cohort, two from HLA-DRB1'01-DQB1'0501 and seven from patients who do not carry any susceptibility MHC allele. These findings suggest that the development of IgAD may be variable depending on the presence of potentially different genes within selected MHC susceptibility haplotypes that interact with the respective disease-causing non-MHC genes. Understanding the interaction between MHC and non-MHC genes and proteins may facilitate identification of the IgAD etiology. In summary, this thesis not only helped to identify the genetic basis of IgAD, but also improved the current diagnostic definition of the disease. Further work, including protein-protein interaction investigations, gene knock-in/out and expression analyses are required to validate the functional role of the novel associations described in this thesis. As IgAD has been shown to be markedly overrepresented among patients with autoimmune diseases, further potential studies will aim to identify the link between IgAD and autoimmunity which may ultimately result in improved patient care.