The original version of this Article contained an error in the spelling of the author Ana Rodríguez-Ramos, which was incorrectly given as Ana Rodríguez Ramos. This has now been corrected in both the PDF and HTML versions of the Article.

Here, we assessed whether 41 SNPs within steroid hormone genes associated with erosive disease. The most relevant finding was the rheumatoid factor (RF)-specific effect of the CYP1B1, CYP2C9, ESR2, FcγR3A, and SHBG SNPs to modulate the risk of bone erosions (P = 0.004, 0.0007, 0.0002, 0.013 and 0.015) that was confirmed through meta-analysis of our data with those from the DREAM registry (P = 0.000081, 0.0022, 0.00074, 0.0067 and 0.0087, respectively). Mechanistically, we also found a gender-specific correlation of the CYP2C9rs1799853T/T genotype with serum vitamin D3 levels (P = 0.00085) and a modest effect on IL1β levels after stimulation of PBMCs or blood with LPS and PHA (P = 0.0057 and P = 0.0058). An overall haplotype analysis also showed an association of 3 ESR1 haplotypes with a reduced risk of erosive arthritis (P = 0.009, P = 0.002, and P = 0.002). Furthermore, we observed that the ESR2, ESR1 and FcγR3A SNPs influenced the immune response after stimulation of PBMCs or macrophages with LPS or Pam3Cys (P = 0.002, 0.0008, 0.0011 and 1.97•10−7). Finally, we found that a model built with steroid hormone-related SNPs significantly improved the prediction of erosive disease in seropositive patients (PRF+ = 2.46•10−8) whereas no prediction was detected in seronegative patients (PRF− = 0.36). Although the predictive ability of the model was substantially lower in the replication population (PRF+ = 0.014), we could confirm that CYP1B1 and CYP2C9 SNPs help to predict erosive disease in seropositive patients. These results are the first to suggest a RF-specific association of steroid hormone-related polymorphisms with erosive disease.

Invasive Aspergillosis (IA) is an opportunistic infection caused by Aspergillus, a ubiquitously present airborne pathogenic mould. A growing number of studies suggest a major host genetic component in disease susceptibility. Here, we evaluated whether 14 single-nucleotide polymorphisms within NFκB1, NFκB2, RelA, RelB, Rel and IRF4 genes influence the risk of IA in a population of 834 high-risk patients (157 IA and 677 non-IA) recruited through a collaborative effort involving the aspBIOmics consortium and four European clinical institutions. No significant overall associations between selected SNPs and the risk of IA were found in this large cohort. Although a hematopoietic stem cell transplantation (HSCT)-stratified analysis revealed that carriers of the IRF4rs12203592T/T genotype had a 6-fold increased risk of developing the infection when compared with those carrying the C allele (OR-Rec=6.24, 95%CI 1.25-31.2, P=0.026), the association of this variant with IA risk did not reach significance at experiment-wide significant threshold. In addition, we found an association of the IRF4AATC and IRF4GGTC haplotypes (not including the IRF4rs12203592T risk allele) with a decreased risk of IA but the magnitude of the association was similar to the one observed in the single-SNP analysis, which indicated that the haplotypic effect on IA risk was likely due to the IRF4rs12203592 SNP. Finally, no evidence of significant interactions among the genetic markers tested and the risk of IA was found. These results suggest that the SNPs on the studied genes do not have a clinically relevant impact on the risk of developing IA.

BackgroundRecent research suggests that genetic variants in the tumor necrosis factor receptor 2 (TNFRSF1B) gene may have an impact on susceptibility to rheumatoid arthritis (RA) and drug response. The present population-based case-control study was carried out to evaluate whether 5 tagging single-nucleotide polymorphisms (SNPs) within the TNFRSF1B gene are associated with the risk of RA and response to antitumor necrosis factor (TNF) drugs.MethodsThe study population included 1412 RA patients and 1225 healthy controls. A subset of 596 anti-TNF-naive RA patients was selected to assess the association of TNFRSF1B SNPs and drug response according to the EULAR response criteria.ResultsWe found that carriers of the TNFRSF1B(rs3397C) allele had a significantly increased risk of developing RA (P=0.0006). Importantly, this association remained significant after correction for multiple testing. We also confirmed the lack of association of the TNFRSF1B(rs1061622) SNP with the risk of RA in the single-SNP analysis (P=0.89), but also through well-powered meta-analyses (P-DOM=0.67 and P-REC=0.37, respectively). In addition, our study showed that carriers of the TNFRSF1B(rs3397C/C), TNFRSF1B(rs1061622G/G), and TNFRSF1B(rs1061631A/A) genotypes had an increased risk of having a worse response to anti-TNF drugs at the level of P less than 0.05 (P=0.014, 0.0085 and 0.028, respectively). We also observed that, according to a log-additive model, carriers of the TNFRSF1B(rs3397C) or TNFRSF1B(rs1061622G) alleles showed an increased risk of having worse response to anti-TNF medications (P=0.018 and 0.0059). However, the association of the TNFRSF1B(rs1061622) SNP only reached marginal significance after correction for multiple testing according to a log-additive model (P=0.0059) and it was not confirmed through a meta-analysis (P-DOM=0.12).ConclusionOur results suggest that the TNFRSF1B(rs3397) variant may play a role in modulating the risk of RA, but does not provide strong evidence of an impact of TNFRSF1B variants in determining response to anti-TNF drugs.

BackgroundRheumatoid arthritis (RA) is a chronic autoimmune disease that arises as a result of the interaction between genetic and environmental factors. A growing body of research suggests that genetic variants within immune-related genes can influence the risk of developing the disease and affect drug response.Materials and methodsTo test this hypothesis, we carried out a comprehensive two-stage case-control study in a White population of 1239 White RA patients and 1229 healthy controls to investigate whether 49 single nucleotide polymorphisms within or near 17 immune-related genes modulate the risk of developing RA and antitumor necrosis factor (anti-TNF) drug response.ResultsLogistic regression analyses showed that carriers of the IL4(rs2070874T) and IL4(rs2243250T) and IL8RB(rs1126580A) alleles or the IL8RB(rs2230054C/C) genotype had a significantly increased risk of developing RA [odds ratio (OR)=1.37, 95% confidence interval (CI) 1.13-1.67, P=0.0016; OR=1.24, 95% CI 1.03-1.49, P=0.020; OR=1.23, 95% CI 1.08-1.41, P=0.002 and OR=1.19, 95% CI 1.04-1.36, P=0.01, respectively]. The association of the IL4 variants was further supported by a meta-analysis including 7150 individuals (P =0.0010), whereas the involvement of the IL8RB locus in determining the susceptibility to RA was also supported by gene-gene interaction analyses that identified significant two-locus and three-locus interaction models including IL8RB variants that act synergistically to increase the risk of the disease (P=0.014 and 0.018). Interestingly, we also found that patients harbouring the IFNG(rs2069705C) allele showed a significantly better response to anti-TNF drugs than those patients carrying the wild-type allele (P=0.0075).ConclusionsOur data suggest that IL4 and IL8RB loci may have a small-effect genetic impact on the risk of developing RA, whereas IFNG might be involved in modulating the response to anti-TNF drugs.

Background Rheumatoid Arthritis (RA) is a chronic autoimmune disease with higher prevalence and worse prognosis in women than men. Objectives We aimed to determine whether 48 single nucleotide polymorphisms (SNPs) within steroid hormone signaling (ESR1, ESR2, PGR, NR1I2, and SHBG), phase I- and II-metabolizing enzyme (HSD17B1, CYP1A1, CYP17A1, CYP1A2, CYP1B1, CYP2C9, CYP2C19, CYP3A4 and GSTP1) and hormone transporter (ABCB1) genes influence on the risk of developing RA and whether genotyping of these variants might help to predict disease risk. Methods The study population included 1357 RA patients and 1219 controls. Logistic regression analyses were performed to determine associations and to predict disease risk. Results We found that carriers of the CYP2C19rs4244285A allele and CYP3A4rs11773597C/C genotype had a significantly increased risk of RA (P=0.019 and P=0.0048) whereas carriers of the CYP2C9rs1057910C and ESR2rs4986938G alleles showed a reduced risk of developing the disease (P=0.036 and P=0.0026). In addition, when a log-additive model was assumed, we observed a significant association for the CYP2C19rs4244285, CYP3A4rs2740574 and ESR2rs4986938 SNPs suggesting an allele-dosage effect of these variants to modulate the risk of RA (P=0.0076, P=0.044 and P=0.0004). Interestingly, a gender-stratified analysis also revealed that women carrying the CYP17A1rs743572G/G genotype or the PGRrs518162A allele showed an increased risk of RA (P=0.026 and P=0.032) whereas an opposite but not significant effect was observed in men (Pinteraction=0.02 and 0.025, respectively). Furthermore, a rheumatoid factor (RF)-stratified analysis showed that seropositive patients carrying the SULT1A1rs9282861A allele had a substantially increased risk of developing RA (P=0.0088) whereas no effect was observed in seronegative patients (P=0.56). Importantly, after correction for multiple testing (P=0.0010), the association of the ESR2rs4986938 SNP with a reduced risk of RA remained statistically significant (P=0.0004) whereas the overall association of CYP2C19rs4244285 and CYP3A4rs2740574 or SULT1A1rs9282861 in seropositive patients reached marginal significance (P=0.0076, P=0.0048 and P=0.0088). Finally, a predictive analysis showed that a model including 3 genetic variants significantly associated with RA had a higher prediction capacity than a model including a similar number of non-significant SNPs (AUROC=0.562 vs. AUROC=0.513; -2log likehood ratio test P=4.24E-07). The predictive analysis showed that the ESR2rs4986938 SNP had the highest predictive capacity (P=0.00015), which along with a previous study demonstrating its correlation with ESR2 mRNA expression suggest a key role of this variant in the modulation of RA risk. Conclusions These findings suggest that SNPs within estrogen-related genes may play a role in modulating susceptibility to RA and can be used to improve the prediction of disease risk. Disclosure of Interest None declared