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.

Flucytosine (5-FC) is a synthetic antimycotic compound, first synthesized in 1957. It has no intrinsic antifungal capacity, but after it has been taken up by susceptible fungal cells, it is converted into 5-fluorouracil (5-FU), which is further converted to metabolites that inhibit fungal RNA and DNA synthesis. Monotherapy with 5-FC is limited because of the frequent development of resistance. In combination with amphotericin B, 5-FC can be used to treat severe systemic mycoses, such as cryptococcosis, candidosis, chromoblastomycosis and aspergillosis. Recently, 5-FC has been combined with newer azole antifungal agents; it also plays an important role in a new approach to the treatment of cancer. The severe side effects of 5-FC include hepatotoxicity and bone-marrow depression. In most patients, these side effects are concentration dependent, predictable, possibly avoidable with close monitoring to maintain 5-FC concentrations at <100 mg/L, and reversible with drug discontinuation or reduction of dose. 5-FC is well absorbed after oral administration, penetrates into body tissues well and is excreted mainly by the kidneys. In renal failure, major dose adjustments have to be made. The most important drug interaction of 5-FC occurs with concomitant administration of 5-FC and nephrotoxic drugs, especially amphotericin B. Owing to the crucial role of glomerular filtration in 5-FC elimination, drugs that impair this mechanism will decrease the elimination of 5-FC and thus prolong its half-life.

Purpose: Several preclinical studies suggested a role for 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) in the treatment of cancer. The objective of this study was to compare the risk of incident cancer between users of statins and users of other cardiovascular medication. Methods: Data were used from the PHARMO database, containing drug dispensing records from community pharmacies and linked hospital discharge records for residents of eight Dutch cities. The study base included all patients with one or more prescriptions for cardiovascular drugs in the period between January 1, 1985 and December 31, 1998. Cases were identified as patients in the study base with a diagnosis of incident cancer and matched with four to six controls on sex, year of birth, geographic region, duration of follow-up, and index date. The analysis was adjusted for diabetes mellitus; prior hospitalizations; comorbidity; and use of diuretics, angiotensin-converting enzyme inhibitors, calcium-channel blockers, nonsteroidal anti-inflammatory drugs, sex hormones, and other lipid-lowering drug therapies. Results: In the study base, 3,129 patients were identified and matched to 16,976 controls. Statin use was associated with a risk reduction of cancer of 20% (adjusted odds ratio [OR], 0.80; 95% CI, 0.66 to 0.96). Our data suggest that statins are protective when used longer than 4 years (adjusted OR, 0.64; 95% CI, 0.44 to 0.93) or when more than 1,350 defined daily doses are taken (adjusted OR, 0.60; 95% CI, 0.40 to 0.91). Conclusion: This observational study suggests that statins may have a protective effect against cancer.