Genome-wide single-nucleotide polymorphism linkage analyses of quantitative rheumatoid arthritis phenotypes in Caucasian NARAC families

Kimberly E Taylor,Christopher I Amos,Wei Chen,Lindsey A Criswell

doi:10.1186/1753-6561-1-s1-s105

Abstract

We applied nonparametric quantitative trait linkage analysis to two rheumatoid arthritis quantitative phenotypes, IgM rheumatoid factor (RF) and anti-cyclic citrullinated peptide autoantibody titer measurements, using 5700 genome-wide Illumina single-nucleotide polymorphism genotypes on 658 Caucasian North American Rheumatoid Arthritis Consortium families. Peak LOD scores for both quantitative traits were located in the human leukocyte antigen region 6p21 (15.8 and 13.8 for RF and anti-cyclic citrullinated peptide, respectively) followed by 11p12 (3.2 and 3.6). In addition, there were LOD scores of 3.2 on 2q32 for RF and 3.6 on 4q24 for anti-cyclic citrullinated peptide. The resulting linkage signals for both phenotypes are very similar to previous results for rheumatoid arthritis as a qualitative variable, with rheumatoid factor measurements being most closely aligned. Interestingly, anti-cyclic citrullinated peptide exhibits a stronger linkage peak on 2p14 than rheumatoid factor and rheumatoid arthritis, and stronger linkage on 4q24. Finally, we used ordered subset analyses to determine if sub-ranges of these two traits increased rheumatoid arthritis linkage signals; however, our analyses did not reveal significant effects of the quantitative traits on rheumatoid arthritis linkage signals in this population.

Highlights

Rheumatoid arthritis (RA) is a chronic autoimmune disease with heterogeneous phenotypes exhibited among affected individuals
In order to directly compare the linkage results for rheumatoid factor (RF) and anti-CCP in regions of interest, we repeated the linkage disequilibrium (LD)-modelled analyses using the subset of affected subjects having measurements for both quantitative traits
We consider IgM rheumatoid factor (RF) and anti-cyclic citrullinated peptide autoantibody titer measurements, both of which are associated with RA but with incomplete and different specificities for the disease

Summary

Introduction

Rheumatoid arthritis (RA) is a chronic autoimmune disease with heterogeneous phenotypes exhibited among affected individuals. It is thought that the difficulty in identifying RA linkage regions may be due in part to its phenotypic heterogeneity, i.e., subtypes of this disease may have different genetic etiologies. Deviates" option because both traits are not normally distributed and the NARAC sample is selected (in particular to contain multi-case RA families). This option necessitates specification of a population mean; in the absence of population data, we chose 11 as the mean for RF and 4.6 as the mean for anti-CCP, as done previously [8]. In order to directly compare the linkage results for RF and anti-CCP in regions of interest, we repeated the LD-modelled analyses using the subset of affected subjects having measurements for both quantitative traits. We consider IgM rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) autoantibody titer measurements, both of which are associated with RA but with incomplete and different specificities for the disease

Methods

Results

Conclusion