RESEARCH - Associations between HLA, PTPN22, CTLA4 and autoantibody status, age at diagnosis, and erosions in RA

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Ann Rheum Dis. Published Online First: 31 July 2007.

doi:10.1136/ard.2007.071662

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Extended Report

Associations between HLA, PTPN22, CTLA4 genotypes and RA phenotypes of

autoantibody status, age at diagnosis, and erosions in a large cohort study

W. Karlson 1*, Lori B. Chibnik 2, Jing Cui 2, M. Plenge 2,

a J. Glass 2, E. Maher 2, 3, Ronenn Roubenoff 4,

Elena Izmailova 5, S. Coblyn 2, E Weinblatt 2 and A.

Shadick 2

1 Brigham & Women's Hospital, United States

2 Brigham and Women's Hospital, United States

3 Amgen Pharmaceuticals, United States

4 BiogenIdec, United States

5 Millenium Pharmaceuticals, United States

Abstract

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

associated with the phenotype of CCP+ 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 if radiographic erosions and age of diagnosis

are associated with these risk alleles.

Methods: 689 RA patients from the Brigham RA Sequential Study (BRASS) were

genotyped for HLA-SE alleles by low-resolution genotyping, and for PTPN22

(rs2476601) and CTLA4 (rs3087243) by Sequenom genotyping. Association

between genotypes and phenotypes for CCP, RF and erosive RA were assessed

with logistic regression models adjusting for age, sex, and disease

duration. Associations between genotype and age at diagnosis of RA were

assessed with general linear models. 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 adjusting for age, sex, and disease

duration, presence of any HLA-SE was strongly associated with CCP+ phenotype

(OR 3.05 (2.18-4.25)), and RF+ phenotype (OR 2.53 (1.83-3.5)); presence of

any PTPN22 T allele was associated with CCP+ phenotype (OR 1.81 (1.24-2.66))

and RF+ phenotype (1.84 (1.27-2.66)). CTLA4 was not associated with CCP or

RF phenotypes in our dataset. While HLA-SE was associated with erosive RA

phenotype (OR 1.52 (1.01-2.17)), this association was no longer significant

after conditioning on CCP. PTPN22 and CTLA4 were not associated with erosive

phenotype. The presence of any HLA-SE was associated with on average 3.6

years earlier diagnosis compared with absence of HLA-SE (41.3 vs. 44.9

years, p=0.003) and PTPN22 was associated with 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.

Conclusion: 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 genotype-phenotype associations between HLA-SE, and

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

phenotype in unconditional analysis, but is no longer significant after

conditioning on CCP, this suggests that CCP is in the causal pathway for

predicting erosive phenotype.

http://ard.bmj.com/cgi/content/abstract/ard.2007.071662v1?papetoc

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