rs9272346
badMag 8.0This is a intergenic variant variant in the HLA-DQA1 gene.
Key Literature Trait Associations
Type 1 Diabetes
rs9272346 is located in the HLA class II region on chromosome 6p21, between HLA-DQA1 and HLA-DRB1. The G allele is strongly associated with increased risk of type 1 diabetes through its linkage with HLA-DQ and HLA-DR haplotypes that encode class II MHC molecules critical for antigen presentation to CD4+ T cells. This locus represents the strongest known genetic risk factor for T1D, accounting for approximately 40-50% of familial clustering, identified in the landmark WTCCC study of 14,000 cases across seven common diseases.
Coeliac disease
rs9272346 was identified as the most significant GWAS hit in a Polish celiac disease cohort (336 cases, 264 controls), localizing within 1 kb of HLA-DQA1 on chromosome 6p21.3. The G allele at this SNP tags the HLA-DQ2.5 haplotype, which is the primary celiac disease risk haplotype; approximately 90% of celiac disease patients carry DQ2 or DQ8. When incorporated into a combined HLA haplotype plus rs9272346 test, diagnostic sensitivity for celiac disease improved from 45.5% to 74% in the Polish population. The mechanistic basis is direct: the HLA-DQ2.5 molecule encoded by the tagged haplotype presents gluten peptides to T cells with exceptional affinity, driving the autoimmune response.
Asthma
rs9272346-A is associated with increased susceptibility to asthma in adults, with genome-wide significant evidence (p=2.2×10⁻⁸) from a GWAS of 3,855 subjects across multiple cohorts. The signal localizes to the HLA-DQA1 locus on chromosome 6p21.3, making HLA-DQA1 the fourth HLA-family member confirmed to be associated with asthma. The association appears stronger in adults than children, suggesting an age-modulated immune mechanism, potentially involving HLA-DQ-mediated sensitization to aeroallergens. Note that the risk allele (A) at this locus for asthma is opposite to the T1D risk allele (G), suggesting distinct haplotypic backgrounds underlie each disease.
▶GWAS Catalog Trait Associations (5)
Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.
GWAS Catalog Trait Associations (5)
Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.
▶Research that mentions this SNP (3)
▶Investigation of genetic risk factors for chronic adult diseases for association with preterm birthAssociationN=1,792Nadia Falah et al.(2013)· Human Genetics
Case-control study of 673 preterm birth (PTB) cases vs 1,119 controls across four maternal cohorts testing 35 SNPs in cardiovascular, inflammatory, and metabolic disease genes. Found 13 statistically significant associations with PTB (P<0.05), more than expected by chance (binomial P=0.02). Most significant was HLA-DQA1 rs9272346 G allele protective effect in US White mothers (P=0.02, OR=0.65, 95% CI 0.46-0.94), which nominally replicated in Danish cohort (P=0.02, OR=0.85, 95% CI 0.75-0.97) but lost significance after correction for multiple testing.
▶Pharmacogenetics: data, concepts and tools to improve drug discovery and drug treatmentReviewJürgen Brockmöller et al.(2008)· European Journal of Clinical Pharmacology
This comprehensive review article traces the evolution of pharmacogenetics from single-gene analysis to whole-genome approaches. It discusses validated pharmacogenetic biomarkers with clinical impact including CYP2D6, CYP2C9, CYP2C19, TPMT, DPD, VKORC1, UGT1A1, and ADRB1/ADRB2, providing examples of how genetic variants affect drug metabolism and response. The paper emphasizes the importance of integrating pharmacogenetic information into clinical practice and drug development.
▶Systematic search for single nucleotide polymorphisms in a lymphoid tyrosine phosphatase gene (PTPN22): Association between a promoter polymorphism and type 1 diabetes in Asian populationsReviewEiji Kawasaki et al.(2006)· American Journal of Medical Genetics Part A
This review examines slowly progressive type 1 diabetes mellitus (SPIDDM), also known as latent autoimmune diabetes in adults (LADA), discussing its pathogenesis, diagnostic markers, and genetic associations. Key findings include T-cell-mediated insulitis and pseudoatrophic islets characteristic of type 1 diabetes, absence of amyloid deposition seen in type 2 diabetes, and identification of multiple genetic susceptibility loci including HLA haplotypes, PTPN22 rs2476601, INS rs689, CTLA4, TCF7L2 rs7903146, ZMIZ1 rs12571751, SH2B3 rs7310615, and PFKFB3 rs1983890. GAD autoantibodies and HLA genotypes are important risk factors for beta-cell failure progression.
Gene information from NCBI Gene. Variant classifications from ClinVar.
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