STXBP6 and B3GNT6 Genes are Associated With Selective IgA Deficiency

• Published in: Frontiers in genetics Vol. 12; p. 736235
• Main Authors: Lim, Che Kang, Bronson, Paola G., Varade, Jezabel, Behrens, Timothy W., Hammarström, Lennart
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 17.12.2021
• Subjects: Genetics; HLA risk allele; immunoglobulin a deficiency; major histocompatibility complex (MHC); non-MHC genes; Stratification; HLA risk allele; non-MHC genes; Stratification; immunoglobulin a deficiency; major histocompatibility complex (MHC)
• ISSN: 1664-8021; 1664-8021
• DOI: 10.3389/fgene.2021.736235

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.