Personalised Genetic Medicine: HLA-DRB1 Amino Acid Positions 11, 71 and 74 Predict Inflammation Level, Disease Activity and Disability in Rheumatoid Arthritis

Stephanie Ling¹, Sebastien Viatte², Mark Lunt³, Alper van Sijl⁴, Lucía Silva Fernández^4,5, Soumya Raychaudhuri^2,6,7, Deborah P.M. Symmons^4,8, Adam Young^9,10, Alex J Macgregor¹¹ and Anne Barton¹², ¹Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Mancheser Academic Health Science Centre, The University of Manchester, Manchester, United Kingdom, ²Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, The University of Manchester, Manchester, United Kingdom, ³Manchester Academic Health Sciences Centre, Arthritis Research UK Centre for Epidemiology, The University of Manchester, Manchester, United Kingdom, ⁴Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, The University of Manchester, Manchester, United Kingdom, ⁵Rheumatology, Complexo Hospitalario Universitario de Ferrol, Ferrol, Spain, ⁶Divisions of Rheumatology and Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, ⁷Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA, ⁸Centre for Musculoskeletal Research, University of Manchester, Arthritis Research UK Centre for Epidemiology, Manchester, United Kingdom, ⁹Rheumatology, ERAS, St Albans City Hospital, St Albans, United Kingdom, ¹⁰School of Life & Medical Sciences, University of Hertfordshire, Hatfield, United Kingdom, ¹¹School of Medicine, Health Policy and Practice, University of East Anglia, Norwich, United Kingdom, ¹²Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, The University Of Manchester, Manchester, United Kingdom

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: Disease Activity, genetics, Inflammation, rheumatoid arthritis (RA) and severity

Session Information

Date: Sunday, November 8, 2015

Title: Genetics, Genomics and Proteomics Poster I

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose:

Amino acid (AA) positions 11, 71 and 74 inside HLA-DRB1 confer susceptibility to rheumatoid arthritis (RA). AAs from these positions form 16 haplotypes, hierarchically classified according to their effect (risk to protective) on RA susceptibility and radiographic severity. However, the mechanism of action remains unknown. The effect of these haplotypes on non-radiographic measures of disease activity/outcomes has not yet been systematically tested.

Hypothesis: The effect of HLA-DRB1 AAs on severity is mediated via inflammation.

Aim: To test association of individual AAs with CRP, tender joint count (TJC), swollen joint count (SJC), DAS28 and HAQ score.

Methods: Genetic data from patients with inflammatory polyarthritis from the Norfolk Arthritis Register (NOAR) were analysed using Generalised Linear Latent and Mixed Modelling to incorporate multiple records per patient over time. The associations of individual AAs, individual positions and individual haplotypes were systematically tested with all outcome variables in univariate and multivariate analyses. Correction for multiple testing in univariate analysis was carried out using the Benjamini-Hochberg (false-discovery rate) method. Validation studies were carried out in the Early Rheumatoid Arthritis Study (ERAS) cohort.

Results:

2,158 patients had genetic and phenotypic data available for analysis in NOAR. Valine at position 11 showed the strongest association with CRP, SJC and DAS28, was marginally associated with HAQ, but not with TJC. The same risk hierarchy observed for susceptibility and radiographic severity was also observed with CRP levels and non-radiographic measures of RA activity/outcome at the AA and haplotype level, although not with TJC.

The valine-containing haplotypes VKA (valine 11, lysine 71, alanine 74) and VRA (valine 11, arginine 71, alanine 74) were significantly associated with increased CRP levels, whereas the serine-containing haplotype SEA (serine 11, glutamic acid 71, alanine 74) was associated with reduced levels. The multivariate haplotype model was significantly associated with CRP levels. When effect sizes for association with CRP were plotted against effect sizes for susceptibility, a significant correlation was observed. A similar pattern was also demonstrated for SJC and DAS28, but not for TJC.

The results replicated in ERAS.

Conclusion: Our findings demonstrate an association between objective disease activity measures and AAs at position 11. At diagnosis, patients with RA can be stratified into 16 genetic categories to predict levels of inflammation, SJC and DAS28 during the disease course. These findings describe a genetic basis for the increased inflammatory response leading to radiographic progression.

Disclosure: S. Ling, None; S. Viatte, None; M. Lunt, None; A. van Sijl, None; L. Silva Fernández, None; S. Raychaudhuri, Pfizer Inc, 2; D. P. M. Symmons, None; A. Young, None; A. J. Macgregor, None; A. Barton, Eli-Lilly, Pfizer, Abbvie, 2.

To cite this abstract in AMA style:

Ling S, Viatte S, Lunt M, van Sijl A, Silva Fernández L, Raychaudhuri S, Symmons DPM, Young A, Macgregor AJ, Barton A. Personalised Genetic Medicine: HLA-DRB1 Amino Acid Positions 11, 71 and 74 Predict Inflammation Level, Disease Activity and Disability in Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/personalised-genetic-medicine-hla-drb1-amino-acid-positions-11-71-and-74-predict-inflammation-level-disease-activity-and-disability-in-rheumatoid-arthritis/. Accessed .

« Back to 2015 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/personalised-genetic-medicine-hla-drb1-amino-acid-positions-11-71-and-74-predict-inflammation-level-disease-activity-and-disability-in-rheumatoid-arthritis/