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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 (PGene = 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.

In delayed-release dimethyl fumarate (DMF)-treated patients, absolute lymphocyte count (ALC) often declines in the first year and stabilizes thereafter; early declines have been associated with development of severe prolonged lymphopenia (SPL). Prolonged moderate or severe lymphopenia is a known risk factor for progressive multifocal leukoencephalopathy (PML); DMF-associated PML is very rare. It is unknown whether genetic predictors of SPL secondary to DMF treatment exist. We aimed to identify genetic predictors of reduced white blood cell (WBC) counts in DMF-treated multiple sclerosis (MS) patients. Genotyping (N = 1,258) and blood transcriptional profiling (N = 1,133) were performed on MS patients from DEFINE/CONFIRM. ALCs were categorized as: SPL, < 500 cells/µL for ≥6 months; moderate prolonged lymphopenia (MPL), < 800 cells/µL for ≥6 months, excluding SPL; mildly reduced lymphocytes, < 910 cells/µL at any point, excluding SPL and MPL; no lymphopenia, ≥910 cells/µL. Genome-wide association, HLA, and cross-sectional gene expression studies were performed. No common variants, HLA alleles, or expression profiles clinically useful for predicting SPL or MPL were identified. There was no overlap between genetic peaks and genetic loci known to be associated with WBC. Gene expression profiles were not associated with lymphopenia status. A classification model including gene expression features was not more predictive of lymphopenia status than standard covariates. There were no genetic predictors of SPL (or MPL) secondary to DMF treatment. Our results support ALC monitoring during DMF treatment as the most effective way to identify patients at risk of SPL.