Abstract
Immunoglobulin A Deficiency (IgAD) is a polygenic primary immune deficiency, with a strong genetic association to the human leukocyte antigen (HLA) region. Previous genome-wide association studies (GWAS) have identified five non-HLA risk loci (IFIH1, PVT1, ATG13-AMBRA1, AHI1 and CLEC16A). In this study, we investigated the genetic interactions between different HLA susceptibility haplotypes and non-MHC genes in IgAD. To do this, we stratified IgAD subjects and healthy controls based on HLA haplotypes (N = 10,993), and then performed GWAS to identify novel genetic regions contributing to IgAD susceptibility. After replicating previously published HLA risk haplotypes, we compared individuals carrying at least one HLA risk allele (HLA-B*08:01-DRB1*03:01-DQB1*02:01 or HLA-DRB1*07:01-DQB1*02:02 or HLA-DRB1*01-DQB1*05:01) with individuals lacking an HLA risk allele. Subsequently, we stratified subjects based on the susceptibility alleles/haplotypes and performed gene-based association analysis using 572,856 SNPs and 24,125 genes. A significant genome-wide association in STXBP6 (rs4097492; p = 7.63 × 10−9) was observed in the cohort carrying at least one MHC risk allele. We also identified a significant gene-based association for B3GNT6 (P Gene = 2.1 × 10–6) in patients not carrying known HLA susceptibility alleles. Our findings indicate that the etiology of IgAD differs depending on the genetic background of HLA susceptibility haplotypes.
Highlights
Immunoglobulin A deficiency (IgAD) is the most common primary immune deficiency (Yazdani et al, 2017), defined as serum levels of IgA ≤ 0.07 g/L in individuals >4 years of age who have normal serum levels of other immunoglobulins (Conley et al, 1999; Picard et al, 2015)
In patients who do not carry any of the major human leukocyte antigen (HLA) susceptibility haplotypes, we identified a significant association with B3GNT6 (p 2.1 × 10–6), which encodes an important precursor in the biosynthesis of mucin-type glycoproteins (Supplementary Table S1)
major histocompatibility complex (MHC) risk haplotypes for Immunoglobulin A Deficiency (IgAD) are neither fully penetrant nor required for disease, it is not yet known whether biological interaction between an MHC susceptibility allele and a non-MHC susceptibility allele contributes to disease onset
Summary
Immunoglobulin A deficiency (IgAD) is the most common primary immune deficiency (Yazdani et al, 2017), defined as serum levels of IgA ≤ 0.07 g/L in individuals >4 years of age who have normal serum levels of other immunoglobulins (Conley et al, 1999; Picard et al, 2015). IgAD exhibits strong familial aggregation typical of a complex polygenic trait, and the strongest genetic associations have been reported in the human major histocompatibility complex (MHC) region The prevalence of autoimmunity, which are strongly associated with the MHC, is strikingly higher in individuals with IgAD (Wang et al, 2011). IgAD is most common in individuals of European ancestry.
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