Projects per year
Abstract
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.
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.
| Original language | English |
|---|---|
| Journal | Annals of the rheumatic diseases |
| Publication status | Accepted/In press - 2 Jul 2025 |
Keywords
- Idiopathic inflammatory myopathies
- human leukocyte antigenqnon-additive effect
- heterozygosity
- allelic interation
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NIHR Manchester Biomedical Research Centre
Bruce, I. (PI), Lord, G. (CoI), Lennon, R. (CoI), Black, G. (CoI), Wedge, D. (CoI), Morris, A. (CoI), Hussell, T. (CoI), Sharrocks, A. (CoI), Stivaros, S. (CoI), Buch, M. (CoI), Gough, J. (CoI), Kostarelos, K. (CoI), Thistlethwaite, F. (CoI), Kadler, K. (CoI), Barton, A. (CoI), Hyrich, K. (CoI), Mcbeth, J. (CoI), O'Neill, T. (CoI), Vestbo, J. (CoI), Simpson, A. (CoI), Singh, S. (CoI), Smith, J. (CoI), Felton, T. (CoI), Murray, C. (CoI), Griffiths, C. (CoI), Cullum, N. (CoI), Rhodes, L. (CoI), Warren, R. (CoI), Paus, R. (CoI), Dumville, J. (CoI), Viros Usandizaga, A. (CoI), Keavney, B. (CoI), Tomaszewski, M. (CoI), Allan, S. (CoI), Body, R. (CoI), Cartwright, E. (CoI), Heagerty, A. (CoI), Kalra, P. (CoI), Miller, C. (CoI), Rutter, M. (CoI), Smith, C. (CoI), Trafford, A. (CoI), Evans, D. (CoI), Crosbie, E. (CoI), Crosbie, P. (CoI), Harvie, M. (CoI), Howell, S. (CoI), Renehan, A. (CoI), Dive, C. (CoI), Blackhall, F. (CoI), Landers, D. (CoI), Krebs, M. (CoI), Cook, N. (CoI), Clarke, R. (CoI), Taylor, S. (CoI), Jorgensen, C. (CoI), Lorigan, P. (CoI), Jayson, G. (CoI), Valle, J. (CoI), Mccabe, M. (CoI), Armstrong, A. (CoI), Freitas, A. (CoI), Illidge, T. (CoI), Choudhury, A. (CoI), Hoskin, P. (CoI), West, C. (CoI), Van Herk, M. (CoI), Faivre-Finn, C. (CoI), Bristow, R. (CoI), Kirkby, K. (CoI), Birtle, A. (CoI), Mackay, R. (CoI), Radford, J. (CoI), Linton, K. (CoI), Higham, C. (CoI), Munro, K. (CoI), Plack, C. (CoI), Arden Armitage, C. (CoI), Bruce, I. (CoI), Moore, D. (CoI), Saunders, G. (CoI), Stone, M. (CoI), Haddock, G. (CoI), Lewis, S. (CoI), Elliott, R. (CoI), Green, J. (CoI), Lovell, K. (CoI), Morrison, A. (CoI), Shaw, J. (CoI), Bucci, S. (CoI), Ainsworth, J. (CoI), Webb, R. (CoI), Newman, W. (CoI), Banka, S. (CoI), Clayton-Smith, J. (CoI), Payne, K. (CoI), Moldovan, R. (CoI), Wynn, R. (CoI) & Jones, S. (CoI)
1/12/22 → 30/11/27
Project: Research
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Arthritis Research UK Centre of Excellence in Epidemiology.
Symmons, D. (PI), Bruce, I. (CoI), Dixon, W. (CoI), Felson, D. (CoI), Hyrich, K. (CoI), Lunt, M. (CoI), Mcbeth, J. (CoI), O'Neill, T. (CoI) & Verstappen, S. (CoI)
1/08/13 → 31/07/18
Project: Research