rs9271366 — HLA-DQA1 eQTL

HLA-DQA1 eQTL — Completing the DR15 Haplotype Panel for Multiple Sclerosis Risk

On chromosome 6, in the most gene-dense stretch of the human genome, sits rs9271366 — an intergenic eQTL¹¹ eQTL
An expression quantitative trait locus: a genetic variant that influences how much of a nearby gene is produced, rather than changing the protein structure itself positioned between HLA-DQA1 and HLA-DRB1. The G allele of rs9271366 tags the DR15 haplotype²² DR15 haplotype
A co-inherited block of HLA alleles: DRB1*15:01 + DQA1*01:02 + DQB1*06:02. These three genes are inherited together so frequently in European populations that detecting one tag SNP can identify the whole block, the classical HLA class II combination that is the single strongest genetic risk factor for multiple sclerosis. Together with rs3135388 (which tags DRB1*15:01 from the DRB1 side), this SNP forms a two-SNP panel for DR15 haplotype detection — capturing the DQA1 regulatory dimension that the DRB1 tag alone cannot fully resolve.

HLA-DQA1 encodes the alpha chain of the HLA-DQ class II heterodimer. This chain partners with HLA-DQB1 to form the antigen-presenting surface on dendritic cells, macrophages, and B cells — the front line of adaptive immune surveillance. The specific combination DQA1*01:02/DQB1*06:02 encoded by the DR15 haplotype creates a peptide-binding groove that, in concert with DRB1*15:01, generates an unusually permissive environment for central nervous system self-antigen presentation. Research has shown that DQA1*01:02 can form a mixed-isotype heterodimer³³ mixed-isotype heterodimer
An HLA-DQ molecule assembled from chains encoded by different classical HLA-DR and DQ loci — in this case DQA1*01:02 pairing with DRB1*15:01 — creating an antigen-presenting complex not predicted from either gene alone with DRB1*15:01, expanding the repertoire of myelin peptides that can be displayed to auto-reactive T cells beyond what each molecule presents independently.

The Mechanism

rs9271366 sits approximately 9,100 bp downstream of HLA-DQA1 and 29,200 bp upstream of HLA-DRB1, placing it in the regulatory landscape shared by both genes. As an eQTL, the G allele is associated with altered HLA class II gene expression within the DR15 haplotype block. The entire block is in strong linkage disequilibrium⁴⁴ linkage disequilibrium
Alleles that are inherited together more often than expected by chance, forming a haplotype. LD means that the G allele of rs9271366 is an excellent proxy for the presence of DRB1*15:01, DQA1*01:02, and DQB1*06:02 on the same chromosome, meaning that detecting the G allele of rs9271366 reliably indicates the presence of the full three-gene MS-risk haplotype. The DRB1 expression data from the companion SNP rs3135388 confirms that A allele carriers (who also carry the DR15 block) show 8.3-fold higher DRB1 and 15.7-fold higher DQB1 expression, flooding antigen-presenting cells with the MS-risk isoform. The rs9271366 G allele captures this same regulatory state from the DQA1 side of the haplotype.

Within the DR15 haplotype, DQA1*01:02 participates in a unique mechanistic pathway. When myelin peptides that bind well to DRB1*15:01 are exhausted or when the standard DRB1-DRA heterodimer is unavailable, the DQA1*01:02/DRB1*15:01 mixed-isotype complex can present oligodendrocyte-specific protein (OSP) epitopes to CD4+ T cells — effectively broadening the antigenic targets available to auto-reactive cells and creating backup pathways for CNS autoimmunity.

The Evidence

The MS association of rs9271366-G reached P = 7 × 10⁻¹⁸⁴ with OR approximately 2.78 in GWAS Catalog aggregated data — one of the most statistically replicated findings in human genetics. A biorepository-linked EHR study⁵⁵ biorepository-linked EHR study
Restrepo et al. analysed 28 autoimmune disease SNPs in electronic health record-linked biobank participants replicated rs9271366 as a hallmark MS SNP with OR 1.91 (p=0.008) and confirmed shared genetic architecture with rheumatoid arthritis and Crohn's disease. An Italian relapsing-remitting MS study⁶⁶ Italian relapsing-remitting MS study
Sorosina et al., 161 untreated RRMS patients with full HLA imputation from WGS found rs9271366 among five MHC loci associated with T-cell receptor diversity — carriers show expanded T-cell clonotypes, consistent with chronic autoantigen-driven T-cell expansion targeting the CNS.

The association extends across autoimmune conditions. For SLE in Hispanic/Dominican patients⁷⁷ SLE in Hispanic/Dominican patients
Liu et al., 201 SLE cases and 205 controls from the Dominican Republic, rs9271366 as a DRB1*15:01 tag SNP showed the highest SLE risk among 13 tested MHC alleles (OR=3.5, p=8.7×10⁻¹⁰). In African American women⁸⁸ African American women
Ruiz-Narvaez et al., Women's Health Study cohort, it was the most strongly associated MHC SNP for SLE (OR=1.70, p=5.6×10⁻⁵), confirming that the DR15 haplotype drives SLE risk across ancestries where this haplotype is present. In Malay and Chinese populations⁹⁹ Malay and Chinese populations
Chai et al., 790 Malaysian subjects, the G allele and GG genotype significantly increased SLE susceptibility, with a DR15-tagged haplotype (GC at rs9271366/rs9275328) reaching genome-wide significance after permutation.

The gene-environment interaction with Epstein-Barr virus documented for the companion DRB1 tag (rs3135388) applies equally here, because both SNPs tag the same haplotype. HLA-DRB1*15:01 acts as a co-receptor for EBV infection of B cells¹⁰¹⁰ HLA-DRB1*15:01 acts as a co-receptor for EBV infection of B cells
Sundqvist et al., demonstrating the mechanistic link between the two strongest known MS risk factors. G allele carriers have more DR15 co-receptor surface available for viral entry, potentially sustaining higher EBV loads, more robust EBNA-1 antibody responses, and higher rates of molecular mimicry against myelin antigens.

Practical Implications

rs9271366 provides complementary information to rs3135388: both tag the DR15 haplotype, but from different positions flanking the DQA1/DRB1 locus. When both SNPs are available (as with WGS or comprehensive genotyping arrays), concordant G-at-rs9271366 and A-at-rs3135388 readings provide higher-confidence DR15 identification than either alone. When only one is available, each serves as a reliable proxy with >95% sensitivity.

The practical actions are shared with the DRB1 tag: vitamin D optimization to dampen the VDRE-driven upregulation of the DR15 allele, and vigilance for early MS symptoms. The vitamin D response element (VDRE) in the HLA-DRB1*15:01 promoter means that vitamin D insufficiency may directly increase expression of the MS-risk isoform in G allele carriers; maintaining serum 25(OH)D above 40 ng/mL is the most evidence-backed modifiable intervention for this haplotype. Approximately 25–30% of Europeans carry at least one DR15 chromosome, but lifetime MS risk remains approximately 1–3% for heterozygotes — HLA is necessary but not sufficient.

Interactions

rs9271366 and rs3135388 are in strong LD and tag the same DR15 haplotype from flanking positions. They are partner SNPs in the GeneOps dual-panel for DR15 detection: concordant results provide the highest confidence, while discordance may reflect genotyping error or, rarely, a partial haplotype. The DQA1*01:02/DRB1*15:01 mixed-isotype heterodimer effect is relevant specifically to rs9271366 as the DQA1-proximal tag: it captures the DQA1*01:02 allele that forms this cross-isotype antigen-presenting complex. Interactions with rs2187668 (HLA-DQ2.5 tag for celiac/T1D) and rs7454108 (HLA-DQ8 tag for T1D) concern distinct haplotype blocks and are not additive for MS risk. The IBD association of rs9271366 reflects a different alternate allele (C) tagging DRB1*15:02, which is unrelated to the G allele DR15 MS-risk signal analyzed here.