Classical HLA class II associations with ALS in Kuwait reveal a DR7-DQ2.2 risk haplotype

Genome-wide association studies have implicated the human leukocyte antigen/major histocompatibility complex (HLA/MHC) region in amyotrophic lateral sclerosis (ALS) susceptibility, and immune dysregulation is increasingly recognised as a modifier of disease course. High-resolution HLA data for ALS remain confined to European and East Asian ancestries. We tested whether classical HLA class I and class II variation contributes to ALS susceptibility in a Kuwaiti cohort.

We analysed 38 unrelated ALS cases (mean age, 57.4 years; 63.2% male) and 150 population-matched controls (mean age, 57.0 years) from Kuwait. HLA-A, -B, -C, -DRB1, -DQA1, and -DQB1 alleles were typed at two-field resolution using HLA-HD from next-generation sequencing (NGS) data. Allele, haplotype, and amino-acid residue associations were tested in BIGDAWG with locus-specific Bonferroni correction, with additional across-locus sensitivity analysis. Significant class II residues were mapped onto AlphaFold 3 structural models and interpreted alongside published class II crystal structures.

No class I allele, haplotype, or residue remained significant after correction. In class II, DQA1*02:01 [odds ratio (OR) = 3.18, 95% confidence interval (CI) 1.67 to 5.95, p _c = 0.0007], DRB1*07:01 (OR = 3.00, 95% CI: 1.58-5.59, p _c = 0.001), and DQB1*02:02 (OR = 2.48, 95% CI: 1.28-4.69, p _c = 0.03) were enriched in cases. The extended haplotype DQA1*02:01~DQB1*02:02~DRB1*07:01 (DR7-DQ2.2) conferred increased odds of ALS (OR = 3.11, 95% CI: 1.53-6.19, p _c = 0.002). Amino-acid residue analysis identified convergent risk positions in DQα1 (positions 47, 52, and 54; OR = 3.18, p _c = 0.006) and DRβ1 (positions 11, 13, 14, 25, and 30; OR = 2.84, p _c = 0.03) that map to the peptide-binding groove and correspond to the defining motifs of DQA1*02:01 and DRB1*07:01.

Using high-resolution NGS-based HLA typing in a Kuwaiti cohort, we identified a class II risk signal for ALS centred on the DR7-DQ2.2 haplotype with convergent residue-level support in the peptide-binding domains. These findings support a contribution of class II-restricted antigen presentation to ALS susceptibility and warrant functional validation and replication in larger, independent Middle Eastern cohorts.