Objectives: Recently, an association was found between Crohn’s disease and the interleukin-23 receptor (IL-23R) gene. Since the IL-23/IL-17 pathway is known to associate with other autoimmune diseases, including rheumatoid arthritis (RA) and systemic sclerosis (SSc), we hypothesised that IL-23R could be a shared susceptibility gene. Methods: Groups of patients with rheumatoid arthritis (n = 412), systemic sclerosis (n = 224), Crohn’s disease (n = 190) and healthy controls (n = 220) were genotyped for rs10889677 (exon-3’UTR C2370A), rs2201841, and rs1884444 variants; the first two have been shown to confer risk for Crohn’s disease. Results: We observed an increased prevalence of the homozygous rs10889677 AA and homozygous rs2201841 CC genotypes both in the Crohn’s disease and in the RA groups as compared to the controls (12.1%, 11.9% vs 5.91%, p<0.05; and 13.2%, 13.1% vs 5.91%, p<0.05), but not in the SSc patients. Logistic regression analysis revealed that bearing these alleles represent risk for the development of rheumatoid arthritis (χ² = 5.58, p = 0.018, OR = 2.15, 95% CI 1.14–4.06 for rs10889677; and χ² = 7.45, p = 0.006, OR = 2.40, 95% CI 1.28–4.51 for rs2201841). The rs1884444 allele, which has been previously reported as neutral for development of Crohn’s disease, was also found neutral for all studied groups in the present study. Conclusions: The data reported here provide direct evidence that some allelic variants or haplogroups of IL-23R represent independent risk factors for rheumatoid arthritis as well as Crohn’s disease, but not for scleroderma.

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.

Prostate cancer is globally the second most commonly diagnosed cancer type in men. Recent studies suggest that mutations in DNA repair genes are associated with aggressive forms of prostate cancer and castration resistance. Prostate cancer with DNA repair defects may be vulnerable to therapeutic targeting by Poly(ADP-ribose) polymerase (PARP) inhibitors. PARP enzymes modify target proteins with ADP-ribose in a process called PARylation and are in particular involved in single strand break repair. The rationale behind the clinical trials that led to the current use of PARP inhibitors to treat cancer was to target the dependence of BRCA-mutant cancer cells on the PARP-associated repair pathway due to deficiency in homologous recombination. However, recent studies have proposed therapeutic potential for PARP inhibitors in tumors with a variety of vulnerabilities generating dependence on PARP beyond the synthetic lethal targeting of BRCA1/BRCA2 mutated tumors, suggesting a wider potential than initially thought. Importantly, PARP-associated DNA repair pathways are also closely connected to androgen receptor (AR) signaling, which is a key regulator of tumor growth and a central therapeutic target in prostate cancer. In this review, we provide an extensive overview of published and ongoing trials exploring PARP inhibitors in treatment of prostate cancer and discuss the underlying biology. Several clinical trials are currently studying PARP inhibitor mono-and combination therapies in the treatment of prostate cancer. Integration of drugs targeting DNA repair pathways in prostate cancer treatment modalities allows developing of more personalized care taking also into account the genetic makeup of individual tumors.