STXBP6 and B3GNT6 Genes are Associated With Selective IgA Deficiency

Area of Science:

• Immunogenetics
• Human genetics
• Primary immunodeficiencies

Background:

• Immunoglobulin A Deficiency (IgAD) is a primary immune deficiency with known genetic links to the human leukocyte antigen (HLA) region.
• Previous genome-wide association studies (GWAS) identified five non-HLA risk loci, but the interaction between HLA and non-MHC genes in IgAD remains unclear.

Purpose of the Study:

• To investigate genetic interactions between HLA susceptibility haplotypes and non-MHC genes in IgAD.
• To identify novel genetic regions contributing to IgAD susceptibility by stratifying subjects based on HLA haplotypes.

Main Methods:

• Stratified 10,993 IgAD subjects and controls by HLA haplotypes.
• Performed genome-wide association studies (GWAS) and gene-based association analysis using 572,856 SNPs and 24,125 genes.
• Compared individuals with and without specific HLA risk alleles/haplotypes.

Main Results:

• Replicated previously identified HLA risk haplotypes.
• Observed a significant genome-wide association in STXBP6 (rs4097492; p = 7.63 × 10⁻⁹) in individuals with at least one MHC risk allele.
• Identified a significant gene-based association for B3GNT6 (P = 2.1 × 10⁻⁶) in patients lacking known HLA susceptibility alleles.

Conclusions:

• The genetic etiology of Immunoglobulin A Deficiency (IgAD) varies depending on the underlying HLA susceptibility haplotype.
• Distinct genetic mechanisms contribute to IgAD in individuals with and without specific HLA risk alleles.