Genome-Wide Association Study of Determinants of Anti-Cyclic Citrullinated Peptide Antibody Titer in Adults with Rheumatoid Arthritis

Jing Cui,Elena S Izmailova,Lindsey A Criswell,Michael E Weinblatt,Elizabeth W Karlson,Anita L Destefano,Alex Parker,Kimberly E Taylor,Ronenn Roubenoff,Robert M Plenge,Nancy A Shadick

doi:10.2119/molmed.2009.00008

Abstract

We carried out a genome-wide association study of genetic predictors of anti-cyclic citrullinated peptide antibody (anti-CCP) level in 531 self-reported non-Hispanic Caucasian Rheumatoid Arthritis (RA) patients enrolled in the Brigham Rheumatoid Arthritis Sequential Study (BRASS). For replication, we then analyzed 289 single nucleotide polymorphisms (SNPs) with P < 0.001 in BRASS in an independent population of 849 RA patients from the North American Rheumatoid Arthritis Consortium (NARAC). BRASS and NARAC samples were genotyped using the Affymetrix 100K and Illumina 550K platforms respectively. Association between SNPs and anti-CCP titer was tested using general linear models. The five most significant SNPs from BRASS all were within the major histocompatibility complex (MHC) region (P < or = 3.5 x 10(-6)). After controlling for the human leukocyte antigen shared epitope (HLA-SE), the top SNPs still yielded P values < 0.0002. In NARAC, a single SNP from the MHC region near BTNL2 and HLA-DRA, rs1980493 (r(2) = 0.85 with the top five SNPs from BRASS), was associated significantly with CCP titer (P = 6.1 x 10(-5)) even after adjustment for the HLA-SE (P = 0.0002). The top SNPs found in BRASS and NARAC had r(2) = 0.46 and 0.64, respectively, to HLA-DRB1 DR3 alleles. These results confirm that the most significant genome region affecting anti-CCP titers in RA is the MHC region. We identified a SNP in moderate linkage disequilibrium (LD) with HLA-DR3, which may influence anti-CCP titer independently of the HLA-SE.

Highlights

Rheumatoid arthritis (RA) is one of the most common autoimmune diseases, affecting 0.5% to 1% of most populations [1]
A total of 575 RA samples were genotyped in this study, including all CCP+ patients enrolled in the Brigham Rheumatoid Arthritis Sequential Study (BRASS) cohort at that time, and 142 CCP– patients
Besides genetic susceptibility analysis in RA, there are studies of genetic associations for anti-CCP level as a quantitative trait. Most of these studies focused on the HLA region [7,10,11, 15,16,17,18], and consistently found that the human leukocyte antigen shared epitope (HLA-shared epitope” (SE)) is associated with higher Anti-cyclic citrullinated peptide (antiCCP) titer

Summary

INTRODUCTION

Rheumatoid arthritis (RA) is one of the most common autoimmune diseases, affecting 0.5% to 1% of most populations [1]. Anti-cyclic citrullinated peptide (antiCCP) antibody is an important biomarker for RA It is as sensitive as, but more specific than, rheumatoid factor for diagnosing RA [6]. We treat anti-CCP antibody titer among RA subjects as a quantitative outcome and proxy for progressive RA in a genome-wide association study (GWAS) to elucidate the genetic basis of anti-CCP titer. Analyses were performed both with and without adjusting for HLA-SE status and HLA-DR3 to identify the additional contribution of genes other than HLA-DRB1 to variability in anti-CCP titer and severity of RA

METHODS

RESULTS

DISCUSSION