Classical HLA Class II Associations With ALS in Kuwait Reveal a DR7–DQ2.2 Risk Haplotype

This study examined whether classical HLA class I and II variation is associated with amyotrophic lateral sclerosis (ALS) susceptibility in a Kuwaiti population.

Prior genome-wide studies implicated the HLA/MHC region in ALS, yet high-resolution classical HLA data have been reported mainly for European and East Asian ancestries.

The authors applied next-generation sequencing (NGS)-based HLA typing to assess allele, haplotype, and residue-level associations in this Middle Eastern cohort.

• Population: 38 unrelated ALS cases (mean age reported 57.4 years; 63.2% male) and 150 population-matched controls (mean age reported 57.0 years) from Kuwait.
• Genotyping: Two-field resolution typing of HLA-A, -B, -C, -DRB1, -DQA1, and -DQB1 using HLA-HD on NGS data.
• Statistical testing: Allele, haplotype, and amino-acid residue associations were evaluated with BIGDAWG; locus-specific Bonferroni correction was applied, and an across-locus sensitivity analysis was performed.
• Structural interpretation: Significant class II residues were projected onto AlphaFold 3 structural models and compared with published class II crystal structures.

Reported effect estimates for these alleles indicate increased odds in cases, with DQA1*02:01 and DRB1*07:01 having the strongest corrected associations.

These residues localize to the peptide-binding groove and align with motifs defining DQA1*02:01 and DRB1*07:01.

• No class I allele, haplotype, or residue association remained significant after multiple-testing correction.
• Class II signals: DQA1*02:01, DRB1*07:01, and DQB1*02:02 showed enrichment in cases after correction.
• Haplotype: The extended class II haplotype DQA1*02:01~DQB1*02:02~DRB1*07:01 (denoted DR7–DQ2.2) was associated with elevated odds of ALS after correction.
• Amino-acid mapping: Residue-level analysis identified shared risk positions in the DQα1 chain (positions 47, 52, 54) and DRβ1 chain (positions 11, 13, 14, 25, 30).

• The pattern of allele, haplotype, and convergent residue findings supports a class II–centred signal implicating antigen presentation in ALS susceptibility within this Kuwaiti sample.
• Structural mapping was used to relate residue associations to peptide-binding domains, consistent with class II functional relevance.

• The report did not include functional validation or replication in independent Middle Eastern cohorts; those steps were explicitly recommended by the authors.
• Sample size and population specificity constrain generalisability; the source did not provide additional demographic or clinical subgroup analyses beyond the summary above.