Associations between APOE genotypes and disease susceptibility, joint damage and lipid levels in patients with rheumatoid arthritis.

Marthe T Maehlen,Tore Saxne,Benedicte A Lie,Tore K Kvien,Annemarie Krabben,Désirée Van Der Heijde,Sella A Provan,Inger Lise Mero,Till Uhlig,Inge C Olsen,Diederik P C De Rooy,Annette H M ,Elisabet Lindqvist,Anne Grete Semb,Yi-Hsiang Hsu

doi:10.1371/journal.pone.0060970

Abstract

ObjectiveApolipoprotein E (APOE) genotypes are associated with cardiovascular disease (CVD) and lipid levels. In rheumatoid arthritis (RA), an association has been found with disease activity. We examined the associations between APOE genotypes and disease susceptibility and markers of disease severity in RA, including radiographic joint damage, inflammatory markers, lipid levels and cardiovascular markers.MethodA Norwegian cohort of 945 RA patients and 988 controls were genotyped for two APOE polymorphisms. We examined longitudinal associations between APOE genotypes and C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) as well as hand radiographs (van der Heijde Sharp Score(SHS)) in 207 patients with 10 year longitudinal data. Lipid levels, cardiovascular markers and history of CVD were compared across genotypes in a cross sectional study of 136 patients. Longitudinal radiological data of cohorts from Lund and Leiden were available for replication. (N = 935, with 4799 radiographs).ResultsIn the Norwegian cohort, associations between APOE genotypes and total cholesterol (TC) and low-density lipoproteins (LDL) were observed (ε2<ε3/ε3<ε4, p = 0.03 and p = 0.02, respectively). No association was present for acute phase reactant or CVD markers, but a longitudinal linear association between APOE genotypes and radiographic joint damage was observed (p = 0.007). No association between APOE genotypes and the severity of joint destruction was observed in the Lund and Leiden cohorts, and a meta- analysis combining all data was negative.Conclusion APOE genotypes are associated with lipid levels in patients with RA, and may contribute to dyslipidemia in some patients. APOE genotypes are not consistently associated with markers of inflammation or joint destruction in RA.

Highlights

Disease severity varies between patients with rheumatoid arthritis (RA), and some studies have indicated that the severity of the disease is influenced by genetic factors [1], [2]
No association was present for acute phase reactant or cardiovascular disease (CVD) markers, but a longitudinal linear association between Apolipoprotein E (APOE) genotypes and radiographic joint damage was observed (p = 0.007)
APOE genotypes are associated with lipid levels in patients with RA, and may contribute to dyslipidemia in some patients

Summary

Results

In the longitudinal analyses a significant linear association was seen for the three APOE genotype groups and radiographic score (APOE linear, p = 0.007, Table 5; model A). These results suggested that carriers of the e2 allele had the highest radiographic score, followed by e3/e3, and with e4 carriers having the least damage (e2 carriers .e3/e3.e4 carriers). This significant association was maintained after adjustments for time, CRP, DMARD treatment, ACPA status, age and gender (p = 0.01, Table 5; model B).

Introduction

Materials and Methods

Discussion