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

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Genetic polymorphisms within the HLA region explain only a modest proportion of anti–cyclic citrullinated peptide (anti-CCP)–negative rheumatoid arthritis (RA) heritability. However, few non-HLA markers have been identified so far. This study was undertaken to replicate the associations of anti-CCP–negative RA with non-HLA genetic polymorphisms demonstrated in a previous study.


The Rheumatoid Arthritis Consortium International densely genotyped 186 autoimmune-related regions in 3,339 anti-CCP–negative RA patients and 15,870 controls across 6 different populations using the Illumina ImmunoChip array. We performed a case–control replication study of the anti-CCP–negative markers with the strongest associations in that discovery study, in an independent cohort of anti-CCP–negative UK RA patients. Individuals from the arcOGEN Consortium and Wellcome Trust Case Control Consortium were used as controls. Genotyping in cases was performed using Sequenom MassArray technology. Genome-wide data from controls were imputed using the 1000 Genomes Phase I integrated variant call set release version 3 as a reference panel.


After genotyping and imputation quality control procedures, data were available for 15 non-HLA single-nucleotide polymorphisms in 1,024 cases and 6,348 controls. We confirmed the known markersANKRD55(meta-analysis odds ratio [OR] 0.80;P = 2.8 × 10−13)andBLK(OR 1.13;P = 7.0 × 10−6) and identified new and specific markers of anti-CCP–negative RA (prolactin [PRL] [OR 1.13;P = 2.1 × 10−6] andNFIA[OR 0.85;P = 2.5 × 10−6]). Neither of these loci is associated with other common, complex autoimmune diseases.


Anti-CCP–negative RA and anti-CCP–positive RA are genetically different disease subsets that only partially share susceptibility factors. Genetic polymorphisms located near thePRLandNFIAgenes represent examples of genetic susceptibility factors specific for anti-CCP–negative RA.

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