rs9275596 — HLA-DQ HLA-DQ Region Peanut Allergy Locus

The HLA-DQ Peanut Allergy Locus: How Your Immune Antigen-Presenting System Shapes Allergen Tolerance

The human immune system must constantly distinguish harmless proteins from genuine threats. At the centre of this process is the HLA (Human Leukocyte Antigen) class II system¹¹ HLA (Human Leukocyte Antigen) class II system
A group of proteins on immune cells that present protein fragments to T cells for surveillance — the molecular "identity card" system, which determines which protein fragments the immune system learns to tolerate and which it mounts a response against. rs9275596 sits in the intergenic region between HLA-DQB1 and HLA-DQA2 on chromosome 6p21.32, tagging the HLA-DQA1*01:02 haplotype — the single strongest common genetic risk factor for peanut allergy identified to date.

The Mechanism

HLA-DQ molecules are heterodimers sitting on the surface of antigen-presenting cells²² antigen-presenting cells
Dendritic cells, macrophages, and B cells that capture proteins, break them into peptide fragments, and display them to T cells such as dendritic cells and B cells. Each HLA-DQ molecule has a peptide-binding groove whose shape — determined by your HLA alleles — dictates which protein fragments it can grip and present. HLA-DQA1*01:02 appears to present peanut protein peptides (particularly from Ara h 2³³ Ara h 2
The major peanut storage protein and the dominant IgE target in clinical peanut allergy) with high efficiency to naïve T cells, biasing the early immune response toward allergic sensitization when the environmental context favours sensitization rather than tolerance.

The SNP itself is intergenic and does not change a protein sequence. Instead, evidence from epigenetic studies⁴⁴ evidence from epigenetic studies
Hong et al. 2015, Nature Communications shows that rs9275596 acts as a quantitative trait locus for DNA methylation at CpG sites in both HLA-DRB1 and HLA-DQB1, altering the expression levels of these nearby genes. The C allele creates a binding site for CEBPE (a transcription factor involved in granulocyte and monocyte development), potentially shifting the balance of HLA class II gene expression and immune cell differentiation in ways that favour allergic sensitization.

The Evidence

Hong et al. (2015)⁵⁵ Hong et al. (2015)
Genome-wide association study identifies peanut allergy-specific loci and evidence of epigenetic mediation in US children. Nature Communications, 2015 conducted the first GWAS of well-characterised food allergy in 2,197 US children and parents of European ancestry from the Chicago Food Allergy Study. rs9275596 reached genome-wide significance (p=6.8×10⁻¹⁰) with an odds ratio of 1.7 (95% CI 1.4–2.1) per C allele. The population-attributable risk was 19–21%, meaning this single HLA locus explains roughly one-fifth of all peanut allergy cases in Europeans. Findings were replicated in an independent European cohort. Both rs9275596 and its companion tag SNP rs7192 were associated with differential DNA methylation at the HLA-DQB1 and HLA-DRB1 genes, suggesting the SNP acts by modulating local chromatin state rather than directly disrupting a coding sequence.

Asai et al. (2018)⁶⁶ Asai et al. (2018)
Canadian genome-wide association study and meta-analysis confirm HLA as a risk factor for peanut allergy independent of asthma. JACI, 2018 extended this finding in the largest peanut allergy GWAS to date, integrating 8 studies including the Canadian Peanut Allergy Registry (850 cases, 926 controls) and 5 replication cohorts. This meta-analysis confirmed the HLA-DQB1 region — centred on rs9275596 — as the principal genetic signal, and critically showed the association was independent of asthma genetic loci, establishing peanut allergy as a distinct genetic entity rather than a subset of atopy.

A 2020 Latvian study⁷⁷ 2020 Latvian study
An Intergenic rs9275596 Polymorphism on Chr. 6p21 Is Associated with Multiple Sclerosis in Latvians. Medicina, 2020 genotyped 273 MS patients and 208 controls, finding the C allele conferred an odds ratio of 1.57 (95% CI 1.20–2.06) for multiple sclerosis — extending the clinical relevance of this locus beyond food allergy to broader HLA-mediated autoimmune risk.

Practical Actions

The clinical utility of this SNP is most significant in two contexts: early-life peanut introduction for infants and allergy immunotherapy planning for affected individuals.

The landmark LEAP trial⁸⁸ LEAP trial
Learning Early About Peanut Allergy — a randomised trial showing early peanut introduction prevents allergy in high-risk infants. NEJM, 2015 established that early peanut introduction (before 11 months) prevents allergy. A striking gene-environment interaction was subsequently identified: HLA-DQA1*01:02 carriers in the peanut-consuming group mounted protective Ara h 2-specific IgG4 responses⁹⁹ protective Ara h 2-specific IgG4 responses
Blocking antibodies that reduce allergen-IgE crosslinking and dampen mast cell activation significantly higher than non-carriers. In other words, the same allele that increases allergy risk when peanut is avoided promotes stronger tolerance when peanut is introduced early — demonstrating that genetic risk is context-dependent and modifiable by dietary environment.

For individuals who have already developed peanut allergy, HLA-DQA1*01:02 status — tagged by the C allele at rs9275596 — predicts superior response to peanut oral immunotherapy (OIT)¹⁰¹⁰ peanut oral immunotherapy (OIT)
Desensitisation therapy involving supervised daily peanut protein consumption at escalating doses. Across the IMPACT (ages 1–4) and POISED (ages 7–55) trials, C allele carriers achieved desensitization at rates of 80–93% versus 61–78% in non-carriers, and sustained unresponsiveness at 52% versus 31%.

Interactions

rs9275596 operates within a broader HLA class II architecture. The most clinically relevant interaction is with rs2187668 (tagging HLA-DQ2.5) and rs7454108 (tagging HLA-DQ8). These three tag SNPs together define the major HLA-DQ susceptibility landscape for autoimmune and allergic conditions. For celiac disease, DQ2.5 and DQ8 are the primary risk haplotypes; for peanut allergy, HLA-DQA1*01:02 (tagged by rs9275596) is the primary risk haplotype. There is partial overlap in the HLA haplotype architecture — understanding which risk haplotypes a person carries provides a more complete picture of their HLA-mediated immune susceptibility profile.