Replication of Associations of Genetic Loci Outside the HLA Region With Susceptibility to Anti–Cyclic Citrullinated Peptide–Negative Rheumatoid Arthritis

INTRODUCTION: Genetic polymorphisms within the HLA region explain only a modest proportion of anti-CCP negative rheumatoid arthritis (RA) heritability. However, few non-HLA markers have been identified so far. Therefore, we aimed to replicate non-HLA markers from a previous study. METHODS: The Rheumatoid Arthritis Consortium International (RACI) densely genotyped 186 autoimmune-related regions in 3,297 anti-CCP negative RA patients and 15,870 controls across 6 different populations using the Illumina ImmunoChip array. Here, we performed a case-control replication study of the most associated anti-CCP negative markers from this discovery study, in an independent cohort of anti-CCP negative UK RA patients; individuals from the ArcOGEN and Wellcome Trust Case Control consortia were used as controls. Genotyping in cases was performed using Sequenom MassArray technology. Genome-wide data from controls was imputed using the 1000 Genomes Phase I integrated variant call set release (v3) as reference panel. RESULTS: After genotyping and imputation quality control procedures, data was available for 15 non-HLA single nucleotide polymorphism (SNPs) in 1024 cases and 6348 controls. We confirmed known markers (ANKRD55, meta-analysis odds ratio (OR): 0.80, p-value=2.8E-13; BLK, OR: 1.13, p=7.0E-06) and identified new and specific markers of anti-CCP negative RA (Prolactin PRL, OR: 1.13, p=2.1E-06; NFIA, OR: 0.85, p=2.5E-06). Neither of these loci is associated with other common, complex auto-immune disease. CONCLUSION: Anti-CCP negative and positive RA are two genetically different disease subsets, only partially sharing susceptibility factors. Genetic polymorphism located near the PRL and NFIA genes represent examples of genetic susceptibility factors specific for anti-CCP negative RA. This article is protected by copyright. All rights reserved.