RESEARCH - Assocations between HLA-SE, PTPN22, CTLA4 genotypes and RA phenotypes of autoantibody status, age at diagnosis and erosions

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Published Online First: 31 July 2007. doi:10.1136/ard.2007.071662

ls of the Rheumatic Diseases 2008;67:358-363

Copyright © 2008 BMJ Publishing Group Ltd & European League Against

Rheumatism

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EXTENDED REPORTS

Associations between Human leukocyte antigen, PTPN22, CTLA4 genotypes

and rheumatoid arthritis phenotypes of autoantibody status, age at

diagnosis and erosions in a large cohort study

E W Karlson 1, L B Chibnik 1, J Cui 1, R M Plenge 1, R J Glass 1, N E

Maher 1, A 2, R Roubenoff 2, E Izmailova 2, J S Coblyn 1, M E

Weinblatt 1, N A Shadick 1

1 Division of Rheumatology, Allergy, and Immunology, Department of

Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA

2 Millenium Pharmaceuticals, Cambridge, Massachusetts, USA

ABSTRACT

Background: HLA-DRB1 shared epitope (HLA-SE), PTPN22 and CTLA4 alleles

are associated with cyclic citrullinated peptide (CCP) and rheumatoid

arthritis (RA).

Objective: We examined associations between HLA-SE, PTPN22, CTLA4

genotypes and RA phenotypes in a large cohort to (a) replicate prior

associations with CCP status, and ( determine associations with

radiographic erosions and age of diagnosis.

Methods: A total of 689 RA patients from the Brigham RA Sequential

Study (BRASS) were genotyped for HLA-SE, PTPN22 (rs2476601) and CTLA4

(rs3087243). Association between genotypes and CCP, rheumatoid factor

(RF) erosive phenotypes and age at diagnosis were assessed with

multivariable models adjusting for age, sex and disease duration.

Novel causal pathway analysis was used to test the hypothesis that

genetic risk factors and CCP are in the causal pathway for predicting

erosions.

Results: In multivariable analysis, presence of any HLA-SE was

strongly associated with CCP+ (odds ratio (OR) 3.05, 95% CI

2.18–4.25), and RF+ (OR 2.53, 95% CI 1.83–3.5) phenotypes; presence of

any PTPN22 T allele was associated with CCP+ (OR 1.81, 95% CI

1.24–2.66) and RF+ phenotypes (OR 1.84, 95% CI 1.27–2.66). CTLA4 was

not associated with CCP or RF phenotypes. While HLA-SE was associated

with erosive RA phenotype (OR 1.52, 95% CI 1.01–2.17), this was no

longer significant after conditioning on CCP. PTPN22 and CTLA4 were

not associated with erosive phenotype. Presence of any HLA-SE was

associated with an average 3.6 years earlier diagnosis compared with

absence of HLA-SE (41.3 vs 44.9 years, p = 0.002) and PTPN22 was

associated with a 4.2 years earlier age of diagnosis (39.5 vs 43.6

years, p = 0.002). CTLA4 genotypes were not associated with age at

diagnosis of RA.

Conclusions: In this large clinical cohort, we replicated the

association between HLA-SE and PTPN22, but not CTLA4 with CCP+ and RF+

phenotypes. We also found evidence for associations between HLA-SE,

and PTPN22 and earlier age at diagnosis. Since HLA-SE is associated

with erosive phenotype in unconditional analysis, but is not

significant after conditioning on CCP, this suggests that CCP is in

the causal pathway for predicting erosive phenotype.

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http://ard.bmj.com/cgi/content/full/67/3/358

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