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

08 May 20264 min read0 viewsJournal Feed

GIST

BackgroundGenome-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.MethodsWe 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.ResultsNo class I allele, haplotype, or residue remained significant after correction.

Clinical Editorial

Study focus and rationale

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.

Cohort, genotyping, and analytic approach

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.

Primary association results

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).

Context and interpretation

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.

Limitations and open questions

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.