A genome-wide association study meta-analysis of more than 100,000 subjects of European and Asian ancestries reveals 42 new risk loci for rheumatoid arthritis, with follow-up studies identifying 98 biological candidate genes that are either already being targeted by drugs or could be in the future. Virtual screening in a genome-wide association study (GWAS) meta-analysis of more than 100,000 subjects of European and Asian ancestries has revealed 42 previously unknown risk loci for rheumatoid arthritis (RA). As a follow-up, the authors developed a new in silico pipeline to identify 98 biological candidate genes at all known RA risk loci. They show that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)1. Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ∼10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2, 3, 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation5, cis-acting expression quantitative trait loci6 and pathway analyses7,8,9—as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes—to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.

Objective: To evaluate the prevalence and predictive value of anti–cyclic citrullinated peptide (anti‐CCP) antibodies in individuals who subsequently developed rheumatoid arthritis (RA) and to determine the relationship to rheumatoid factor (RF) of any isotype.Methods: A case–control study was nested within the Northern Sweden Health and Disease Study and the Maternity cohorts of Northern Sweden. Patients with RA were identified among blood donors whose samples had been taken years before the onset of symptoms. Control subjects matched for age, sex, date of sampling, and residential area were selected randomly from the same cohorts. Anti‐CCP antibody and RFs were determined using enzyme immunoassays.Results: Eighty‐three individuals with RA were identified as having donated blood before presenting with any symptoms of joint disease (median 2.5 years [interquartile range 1.1–4.7] before RA). In samples obtained before the onset of RA, the prevalence of autoantibodies was 33.7% for anti‐CCP, 16.9% for IgG‐RF, 19.3% for IgM‐RF, and 33.7% for IgA‐RF (all highly significant compared with controls). The sensitivities for detecting these autoantibodies >1.5 years and ≤1.5 years before the appearance of any RA symptoms were 25% and 52% for anti‐CCP, 15% and 30% for IgM‐RF, 12% and 27% for IgG‐RF, and 29% and 39% for IgA‐RF. In conditional logistic regression models, anti‐CCP antibody and IgA‐RF were found to be significant predictors of RA.Conclusion: Anti‐CCP antibody and RFs of all isotypes predated the onset of RA by several years. The presence of anti‐CCP and IgA‐RF predicted the development of RA, with anti‐CCP antibody having the highest predictive value. This indicates that citrullination and the production of anti‐CCP and RF autoantibodies are early processes in RA.

Objective: To investigate whether smoking and HLA–DR shared epitope (SE) genes may interact in triggering immune reactions to citrulline‐modified proteins.Methods: In a case–control study involving patients with recent‐onset rheumatoid arthritis (RA), we studied interactions between a major environmental risk factor (smoking), major susceptibility genes included in the SE of HLA–DR, and the presence of the most specific autoimmunity known for RA (i.e., antibodies to proteins modified by citrullination). Immunostaining for citrullinated proteins in cells from bronchoalveolar lavage fluid was used to investigate whether smoking is associated with citrullination in the lungs.Results: Previous smoking was dose‐dependently associated with occurrence of anticitrulline antibodies in RA patients. The presence of SE genes was a risk factor only for anticitrulline‐positive RA, and not for anticitrulline‐negative RA. A major gene–environment interaction between smoking and HLA–DR SE genes was evident for anticitrulline‐positive RA, but not for anticitrulline‐negative RA, and the combination of smoking history and the presence of double copies of HLA–DR SE genes increased the risk for RA 21‐fold compared with the risk among nonsmokers carrying no SE genes. Positive immunostaining for citrullinated proteins was recorded in bronchoalveolar lavage cells from smokers but not in those from nonsmokers.Conclusion: We identified an environmental factor, smoking, that in the context of HLA–DR SE genes may trigger RA‐specific immune reactions to citrullinated proteins. These data thus suggest an etiology involving a specific genotype, an environmental provocation, and the induction of specific autoimmunity, all restricted to a distinct subset of RA.

Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease in which the risk of disease is influenced by complex genetic and environmental contributions. Alleles of HLA-DRB1, IRF5, and STAT4 are established susceptibility genes; there is strong evidence for the existence of additional risk loci. We genotyped more than 500,000 single-nucleotide polymorphisms (SNPs) in DNA samples from 1311 case subjects with SLE and 1783 control subjects; all subjects were North Americans of European descent. Genotypes from 1557 additional control subjects were obtained from public data repositories. We measured the association between the SNPs and SLE after applying strict quality-control filters to reduce technical artifacts and to correct for the presence of population stratification. Replication of the top loci was performed in 793 case subjects and 857 control subjects from Sweden. Genetic variation in the region upstream from the transcription initiation site of the gene encoding B lymphoid tyrosine kinase (BLK) and C8orf13 (chromosome 8p23.1) was associated with disease risk in both the U.S. and Swedish case–control series (rs13277113; odds ratio, 1.39; P=1×10⁻¹⁰) and also with altered levels of messenger RNA in B-cell lines. In addition, variants on chromosome 16p11.22, near the genes encoding integrin alpha M (ITGAM, or CD11b) and integrin alpha X (ITGAX), were associated with SLE in the combined sample (rs11574637; odds ratio, 1.33; P=3×10⁻¹¹). We identified and then confirmed through replication two new genetic loci for SLE: a promoter-region allele associated with reduced expression of BLK and increased expression of C8orf13 and variants in the ITGAM–ITGAX region.

Jane Worthington and colleagues use a high-density genotyping chip to identify new susceptibility loci for rheumatoid arthritis and examine genetic overlap with other autoimmune diseases. Their results increase the number of confirmed rheumatoid arthritis risk loci in individuals of European ancestry and refine the location of many previously identified association signals to single genes. Using the Immunochip custom SNP array, which was designed for dense genotyping of 186 loci identified through genome-wide association studies (GWAS), we analyzed 11,475 individuals with rheumatoid arthritis (cases) of European ancestry and 15,870 controls for 129,464 markers. We combined these data in a meta-analysis with GWAS data from additional independent cases (n = 2,363) and controls (n = 17,872). We identified 14 new susceptibility loci, 9 of which were associated with rheumatoid arthritis overall and five of which were specifically associated with disease that was positive for anticitrullinated peptide antibodies, bringing the number of confirmed rheumatoid arthritis risk loci in individuals of European ancestry to 46. We refined the peak of association to a single gene for 19 loci, identified secondary independent effects at 6 loci and identified association to low-frequency variants at 4 loci. Bioinformatic analyses generated strong hypotheses for the causal SNP at seven loci. This study illustrates the advantages of dense SNP mapping analysis to inform subsequent functional investigations.