| Source: |
Chen, G, Zhu, C, Chinoy, H, Amos, C I, Lamb, J A, Amos, C, Zhu, C, Benveniste, O, Chinoyv, H, Bleecker, J L D, Paepe, B D, Doria, A, Geiger, Z, Gregersen, P K, Hanna, M G, Lamb, J A, Limaye, V, Lundberg, I, Padyukov, L, Machado, P, Mathiesen, P, Maurer, B, Miller, F W, Rider, L, Shiffenbauer, A, Molberg, Ø, Pachman, L, Radstake, T, Reed, A M, Rothwell, S, Selva-O’Callaghan, A, Vencovský, J & Wedderburn, L R 2025, 'HLA Loci Heterozygosity Modulates Genetic Risk in Idiopathic Inflammatory Myopathies', Annals of the rheumatic diseases, vol. 84, no. 10, pp. .... |
| Description: |
Objectives: The idiopathic inflammatory myopathies (IIMs) are rare autoimmune disorders. Genetic association studies have highlighted the role of human leukocyte antigen (HLA) polymorphisms in IIM. We aimed to characterise the non-additive effects (dominance and interaction) of HLA alleles on IIM risk. Methods: This study included a total of 3,206 IIM cases and 11,697 controls of European ancestry. HLA alleles were imputed using a multi-ancestry HLA reference panel. Logistic regressions were conducted to estimate the non-additive effects of HLA alleles. Clinical subgroup analysis, calculation of phenotypic variance explained, and stepwise conditional analyses were conducted to further characterise these effects. Results: We identified significant non-additive effects in five HLA genes, particularly in the core alleles of ancestral haplotype 8.1 (8.1 AH), including HLA-B*08:01 (P=3.93×10 -13 ), HLA-C*07:01 (P=3.14×10 -8 ), HLA-DQA1*05:01 (P=3.03×10 -9 ), HLA-DQB1*02:01 (P=3.53×10 -23 ), and HLA-DRB1*03:01 (P=8.47×10 -21 ). Notable risk difference between heterozygotes and homozygotes was observed in IIM, such as HLA-DRB1*03:01 (homozygote OR=2.17; heterozygote OR=3.13). In the interaction model, HLA-DQA1 and HLA-DRB1 showed specific significant allelic interactions. The non-additive effect model explained a larger proportion of phenotypic variance than the model with additive effects alone. Conditional analysis indicated the independent non-additive effect of HLA-DRB1*03:01 in 8.1 AH and amino acid residue Arg-74 in HLA-DRB1 . Conclusions: This study identified significant non-additive effects within the HLA region in IIM. A genetic risk model including non-additive effects could provide more accurate individual risk estimates. These findings highlight a complex role of HLA heterozygosity in the development of IIM and support further research into HLA non-additive effects with clinical relevance. |