rs1042544 (HLA-DPB1): Pediatric Vasculitis Variant

Key takeaways

• rs1042544 sits within HLA-DPB1 (Human Leukocyte Antigen DP beta 1), a gene in the HLA region long associated with immune susceptibility.
• A specific allele at this locus (HLA-DPB1*04:01) was significantly associated with pediatric ANCA-associated vasculitis (a rare, immune-driven inflammation of blood vessels) in children of European ancestry, with an odds ratio of 3.5.
• The same allele showed a non-significant opposite-direction effect in adults (odds ratio 0.4), suggesting age may modify how this genetic signal relates to the condition.
• GTEx data show rs1042544 is linked to reduced expression of HLA-DPA1 in fibroblasts and RPL32P1 across multiple tissues, and to increased expression of a nearby uncharacterized gene in lung and nerve tissue.

What the research says A genome-wide association study (GWAS, a method scanning the full genome for variants linked to a condition) of 63 pediatric patients with ANCA-associated vasculitis (AAV, a rare, life-threatening inflammation of blood vessels associated with antineutrophil cytoplasmic antibodies) and 315 population-matched controls of European ancestry found a significant association between the HLA-DPB1*04:01 allele and pediatric AAV at an odds ratio of 3.5, with a stronger signal in children positive for proteinase 3-ANCA than in those positive for myeloperoxidase-ANCA (the two main antibody-defined subtypes of the disease). In a follow-up adult AAV cohort, the same allele was the most highly associated among HLA alleles but did not reach statistical significance, and it trended in the opposite direction (OR 0.4), a discrepancy the authors acknowledge while concluding that childhood- and adult-onset disease likely share a common genetic predisposition. T cell receptor and interferon signaling pathways were also found to be enriched in the pediatric cohort, providing mechanistic context for the locus association.

Reported associations

• Pediatric ANCA-associated vasculitis: Significant positive association with the HLA-DPB1*04:01 allele in children (n = 63 cases, n = 315 controls, OR 3.5, European ancestry). The signal was stronger in proteinase 3-ANCA-positive children than in myeloperoxidase-ANCA-positive children.
• Adult ANCA-associated vasculitis: In a follow-up adult cohort, the same allele was the most highly associated among HLA alleles but did not reach statistical significance, and the direction of effect was reversed (OR 0.4).
• T cell receptor and interferon signaling pathways: Both pathways were enriched in the pediatric AAV cohort, suggesting a role for immune dysregulation as a mechanism underlying the HLA-DPB1 association.

Evidence quality The pediatric GWAS had a small sample (63 cases, 315 controls), a constraint the authors attribute to the rarity of AAV in children. The pediatric association was genome-wide significant with an OR of 3.5. However, the adult replication cohort did not confirm the signal, and the direction of effect was reversed (OR 0.4, non-significant). The study authors note this discrepancy while still interpreting both cohorts as consistent with a shared genetic predisposition across age groups. This conflicting directionality reduces confidence in generalizing the pediatric finding, and the evidence as a whole should be considered preliminary given the limited sample size and the unreplicated adult result. Enrichment of T cell receptor and interferon signaling pathways adds biological plausibility but does not resolve the replication uncertainty.

Tissue-specific expression effects

• HLA-DPA1: rs1042544 is associated with reduced expression in cultured fibroblasts (skin-derived cells commonly used in laboratory studies) GTEx Portal.
• RPL32P1: rs1042544 is associated with reduced expression in EBV-transformed lymphocytes (immune cells grown in a lab setting), subcutaneous adipose (fat) tissue, sun-exposed skin, tibial nerve, and lung GTEx Portal.
• ENSG00000291111: rs1042544 is associated with increased expression of this currently uncharacterized gene in lung and tibial nerve tissue GTEx Portal.

Lifestyle considerations No lifestyle considerations on file for this variant.