Risk Of RA Research Articles

Lipid management in rheumatoid arthritis: a position paper of the Working Group on Cardiovascular Pharmacotherapy of the European Society of Cardiology.

Rheumatoid arthritis (RA) is associated with increased cardiovascular morbidity, partly due to alterations in lipoprotein quantity, quality and cell cholesterol trafficking. Although cardiovascular disease significantly contributes to mortality excess in RA, cardiovascular prevention has been largely insufficient. Because of limited evidence, optimal strategies for lipid management (LM) in RA have not been determined yet, and recommendations are largely based on expert opinions. In this position paper, we describe abnormalities in lipid metabolism and introduce a new algorithm for estimation of cardiovascular risk (CVR) and LM in RA. The algorithm stratifies patients according to RA-related factors impacting CVR (such as RA activity and severity and medication). We propose strategies for monitoring of lipid parameters and treatment of dyslipidaemia in RA (including lifestyle, statins and other lipid-modifying therapies, and disease modifying antirheumatic drugs). These opinion-based recommendations are meant to facilitate LM in RA until more evidence is available.

Disease progression in relation to pre-onset parity among women with rheumatoid arthritis

ObjectiveRheumatoid arthritis (RA) often ameliorates during pregnancy and flares postpartum, but the relationship of pregnancy and childbirth to RA prognosis is unclear. We examined RA severity for association with parity prior to RA onset and asked whether time from birth (latency) and/or the mother's HLA genotype influenced results. MethodsA cohort study was conducted of 222 women previously identified in a prospective study of newly diagnosed RA, who returned for follow-up evaluation a median of 8 years later. Stratified analyses using Mantel-Haenszel methods were conducted to evaluate 5 RA severity measures based on hand and wrist radiographs, physical exams, and Health Assessment Questionnaires for association with parity. ResultsOverall, we observed little evidence of altered risk of progression to severe RA in relation to pre-onset parity, adjusting for RA onset age and time to follow-up. Stratifying parous women who had only live births by latency (<15 years/15+ years) showed no difference in risk of severe RA compared to nulligravid women. Live birth deliveries were significantly protective for women with 0 but not for those with 1 or 2 copies of the RA risk-associated HLA-DRB1 shared epitope sequence for erosion score (RR 0.26 95% CI 0.09–0.89) and joint count (RR 0.28 95% CI 0.09–0.87). ConclusionWe observed little evidence of difference in severe RA by pre-onset parity overall. However, among women not predisposed to RA by possessing the risk-associated HLA genotype, parous women who had only live births had lower risk of progression to severe RA as measured by erosion score and joint count.

1245-P: The Association of Glucose Variability during the Last Day of Hospitalization and 30-Day Readmission in Adults with Diabetes

Objective: Thirty-day hospital readmission (30-day RA) rates are a metric of healthcare quality. Limited data is available, whether increased glucose variability (GV) during the last day of hospital stay is associated with an increased risk of 30-day RA. Design: Nationwide cohort of 1,042,859 admissions of patients with diabetes in the non-critical care setting in 129 Veteran Affairs hospitals, between 2001-2014. Coefficient of Variation (CV) was measured using point of care- glucometer values and was used as measurement of GV, divided into ten equal categories (tentiles). Covariates, including demographics, socio-economic and hospital related factors and up to 30 comorbidities were collected. Poisson regression was used to determine if CV during the last stay day of the hospitalization was associated with 30-day RA. Results: After adjusting for age, gender and race (Model 1), there was a gradual increase in 30-day RA ratio among admissions with higher CV. Following adjusting for all the covariates collected (Model 2), only admissions with the highest CV demonstrated an increased 30-day RA. The rate ratios and 95% CIs were 1.049 (1.026, 1.073, p&amp;lt;0.0001), 1.038 (1.015,1.061, p=0.0011), 1.065 (1.042,1.089, p&amp;lt;0.0001), for the 8th, 9th and the 10th tentiles respectively, compared to those with CV in the 1st tentile. In Model 3, after adjusting for covariates used in Model 2 and for hypoglycemia, results remained statistically significant for those admissions with the highest CV [rate ratios and 95% CIs are 1.044 (1.021,1.068, p=0.0001), 1.028 (1.006,1.052, p=0.014), 1.042 (1.018,1.067, p=0.0005) for the 8th, 9th and the 10th tentiles]. Conclusions: Higher glucose variability during the last day of hospitalization was associated with increased 30-day RA rates after adjustment for multiple covariates and hypoglycemia. Disclosure E. Spanakis: None. L.G. Singh: None. T. Siddiqui: None. J.D. Sorkin: None. G. Notas: None. M.F. Magee: Consultant; Self; Mytonomy. Research Support; Self; Lilly Diabetes, Mytonomy, Sanofi. Speaker's Bureau; Self; PRIMED. J.C. Fink: None. M. Zhan: None. G.E. Umpierrez: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc. Research Support; Self; AstraZeneca, Merck &amp; Co., Inc., Novo Nordisk Inc., Sanofi US. Funding U.S. Department of Veterans Affairs (1I01CX001825-01)

IL‐7R gene polymorphisms among patients with rheumatoid arthritis: A case–control study

BackgroundRheumatoid arthritis (RA) is the most common inflammatory disease which refers to bony erosions and joint destruction largely caused by genetic factors. Our study aimed to explore whether interleukin‐7 receptor (IL‐7R) gene polymorphisms influenced RA risk in the Han Chinese population.MethodsFive single nucleotide polymorphisms (SNPs) in IL‐7R gene were successfully genotyped using Agena MassARRAY platform. The associations between IL‐7R polymorphisms and RA were evaluated by the Chi‐squared test, T test, genetic model analysis, and haplotype analysis. We calculated odds ratios (ORs) and 95% confidence intervals (95% CIs) using logistic regression analysis.ResultsRs969129 and rs6451231 in the IL‐7R gene were associated with an increased risk of RA in the allele model (OR = 1.25, 95% CI = 1.05–1.49, p = 0.013; OR = 1.23, 95% CI = 1.03–1.48, p = 0.023), respectively. In the genetic models, rs969129 and rs6451231 were associated with an increased risk of RA. After stratification analysis by age, rs969129 and rs6451231 were associated with an increased risk of RA in patients (age <54). After stratification analysis by gender, rs6451231 was associated with an increased risk of RA in males, while rs969129 was found to be associated with an elevated risk of RA in females. And there was a strong linkage disequilibrium among the four SNPs (rs969129, rs118137916, rs10053847, and rs6451231).ConclusionThese results suggested rs969129 and rs6451231 in the IL‐7R gene were associated with an increased risk of RA in the Han Chinese population.

Study of vascular endothelial growth factor A gene polymorphisms in association with Iranian rheumatoid arthritis patients

BackgroundRheumatoid arthritis (RA) is an autoinflammatory disease, in which synovial cells in the joints produce a complex network of cytokines. Vascular endothelial growth factor (VEGF) has been reported to be overexpressed in RA patients. The aim of this study was to investigate the possible association of three single nucleotide polymorphisms (SNPs) of VEGFA gene with susceptibility to RA in Iranian population. MethodsThe study group was comprised of of 300 RA patients and 249 age, sex, and ethnicity matched healthy individuals. Three SNPs of rs2010963, rs833061, and rs3025039 in the VEGFA gene were genotyped in both case and control groups using TaqMan Real-time PCR allelic discrimination technique. ResultsFrequencies of neither the alleles nor genotypes of all three SNPs in VEGFA gene displayed significant differences between RA patients and healthy controls. Four haplotypes of TGC, TCC, CGC, and CGT (rs833061 T/C-rs2010963 G/C-rs3025039 C/T) had statistically significant association with the risk of RA (but without enough power). Patients with the three genotypes of rs833061 SNP show significantly different Rheumatoid factor (RF) levels. ConclusionsThe alleles and genotypes of VEGFA gene polymorphisms were not associated with the disease susceptibility in Iranian RA population.

Microbiota-derived butyrate limits the autoimmune response by promoting follicular regulatory T cells

Abstract Rheumatoid arthritis (RA) is a chronic debilitating autoimmune disorder with a high prevalence, especially in industrialized countries. Dysbiosis of the intestinal microbiota has been observed in RA patients. For instance, new-onset untreated RA is associated with the expansion of Prevotellaceae and the under representation of the Clostridiumcluster XIVa, including Lachnospiraceae, which are major butyrate producers in the gut, although the pathological relevance has remained obscure. Here, we report that microbiota fermentation product butyrate controls the development of autoimmune arthritis in the host. We found that systemic autoantigen immunization causes hyperplasia of gut-associated lymphoid tissues by amplifying the germinal center (GC) reaction. Butyrate mitigated these pathological events by increasing Bcl-6+CXCR5+CD25−Foxp3+ follicular regulatory T (TFR) cells. Butyrate directly induced the differentiation of functional TFR cells by enhancing histone acetylation in TFR cell marker genes. The adoptive transfer of butyrate-induced TFR cells prevented autoimmune arthritis in mice. Notably, TFR cells induced by butyrate suppressed the development of autoreactive follicular helper T (TFH) and GCB cells and their migration from GALT into articulation-draining lymph nodes (DLNs). Accordingly, microbiota-derived butyrate serves as an environmental cue to enhance TFR cells which suppress the GC reaction and autoantibody production in the systemic lymphoid tissue, eventually ameliorating autoimmune arthritis. Our findings provide mechanistic insights into the link between the gut microbiota and RA risk.

Prevotella copri in individuals at risk for rheumatoid arthritis

ObjectivesRheumatoid arthritis (RA) has been associated with a relative expansion of faecal Prevotellaceae. To determine the microbiome composition and prevalence of Prevotella spp. in a group of individuals at increased...

Studying the Association between STAT4 Gene Polymorphism and Susceptibility to Rheumatoid Arthritis Disease: An Updated Meta-Analysis.

STAT4 is a transcription factor that plays a role in various cytokine signaling pathways and in T cell subsets differentiation. Several studies have reported STAT4 gene polymorphism in association with various autoimmune diseases. To evaluated the association between STAT4 rs7574865 SNP and RA risk by meta-analysis. Two major databases, namely Scopus and PubMed, were searched to find studies investigating the STAT4 polymorphism and RA in different populations up to November 2017. Association between STAT4 polymorphism and RA were analyzed using pooled odds ratio (OR) and their corresponding 95% CI. In this meta-analysis, 21 population studies (16 papers) comprising 15,732 cases and 15641 healthy subjects evaluating the STAT4 gene rs7574865 SNP were included based on inclusion criteria. Herein, we found a significant positive association between minor T allele as well as different genotypes with the risk of RA. In summary, this study revealed an association between STAT4 gene rs7574865 SNP and risk of RA.

Polymorphisms at phase I-metabolizing enzyme and hormone receptor loci influence the response to anti-TNF therapy in rheumatoid arthritis patients.

The aim of this case-control study was to evaluate whether 47 single-nucleotide polymorphisms (SNPs) in steroid hormone-related genes are associated with the risk of RA and anti-TNF drug response. We conducted a case-control study in 3 European populations including 2936 RA patients and 2197 healthy controls. Of those, a total of 1985 RA patients were treated with anti-TNF blockers. The association of potentially interesting markers in the discovery population was validated through meta-analysis with data from DREAM and DANBIO registries. Although none of the selected variants had a relevant role in modulating RA risk, the meta-analysis of the linear regression data with those from the DREAM and DANBIO registries showed a significant correlation of the CYP3A4rs11773597 and CYP2C9rs1799853 variants with changes in DAS28 after the administration of anti-TNF drugs (P = 0.00074 and P = 0.006, respectively). An overall haplotype analysis also showed that the ESR2GGG haplotype significantly associated with a reduced chance of having poor response to anti-TNF drugs (P = 0.0009). Finally, a ROC curve analysis confirmed that a model built with eight steroid hormone-related variants significantly improved the ability to predict drug response compared with the reference model including demographic and clinical variables (AUC = 0.633 vs. AUC = 0.556; PLR_test = 1.52 × 10-6). These data together with those reporting that the CYP3A4 and ESR2 SNPs correlate with the expression of TRIM4 and ESR2 mRNAs in PBMCs (ranging from P = 1.98 × 10-6 to P = 2.0 × 10-35), and that the CYP2C9rs1799853 SNP modulates the efficiency of multiple drugs, suggest that steroid hormone-related genes may have a role in determining the response to anti-TNF drugs.KEY POINTS• Polymorphisms within the CYP3A4 and CYP2C9 loci correlate with changes in DAS28 after treatment with anti-TNF drugs.• A haplotype including eQTL SNPs within the ESR2 gene associates with better response to anti-TNF drugs.• A genetic model built with eight steroid hormone-related variants significantly improved the ability to predict drug response.

When does the increased mortality risk appear in rheumatoid arthritis? A distributed data analysis comparing mortality in two Canadian provinces

IntroductionRheumatoid arthritis (RA) is chronic inflammatory arthritis. For decades studies showed that RA patients died earlier than their general population counterparts. Some inception cohorts have failed to detect an increased mortality risk, possibly due to limited follow-up or to improvement in mortality risk in cohorts of more recent onset.&#x0D; Objectives and ApproachWe evaluated mortality risk in RA patients and estimated when the increased risk appears. Using a common protocol, we conducted distributed analyses using administrative data, of incident RA patients in British Columbia (BC) and Ontario (ON) over 2000-2015. We identified all RA patients (using validated criteria), and identified non-RA comparators, matched 1:2 on age, sex and index years. Adjusted hazard ratios (HRs) were estimated using multivariable Cox regression, controlling for comorbidities and other factors. To estimate when the increased risk appeared we included an interaction with follow-up time, to detect if and how the HR varied by RA duration.&#x0D; ResultsAmong 13834 RA patients in BC (27668 comparators), 66% were female with a mean age of 58 years at cohort entry. Among 27405 RA patients in ON (54810 comparators), 70% were female with a mean age of 56 years. The prevalence of individual comorbidities was comparable across RA cohorts. During follow-up, 23% of RA patients in each province died, with corresponding crude mortality rates of 2.3 deaths per 100 person-years in both provinces. Multivariable analyses detected an increased mortality risk in RA by 6 years of follow-up, with a linear relationship suggesting further increase over time. By 10 years, the adjusted HR was 1.14 (95% CI 1.07,1.22) in BC and 1.13 (95% CI 1.08,1.18) in ON.&#x0D; Conclusion/ImplicationsIn 2 large Canadian RA inception cohorts, a small increased mortality risk appeared after 6 years of RA duration and increased to a 14% (in BC) and 13% (in ON) increased mortality risk after 10 years, suggesting increased efforts to prevent disease progression and optimizing comorbidity management are needed.

Passive smoking in childhood increases the risk of developing rheumatoid arthritis.

To investigate the link between smoking status, including childhood and adult passive exposure, and the risk of incident RA. The French E3N cohort includes 98 995 female volunteers prospectively followed since 1990. Self-administered questionnaires sent every 2-3 years collected medical events, general, lifestyle and environmental characteristics. RA diagnoses were collected in three successive questionnaires and confirmed if women received reimbursement for an RA-specific medication. The risk of incident RA was estimated using an age-adjusted Cox model that considers smoking status as a time-dependent variable. Among 71 248 women, 371 incident RA cases were confirmed. Ever-smokers not exposed to passive smoking had an increased risk of RA [1.38 (95% CI 1.10, 1.74)]. In never-smokers, passive smoking exposure during childhood was associated with a borderline increased risk of RA in the same range as active smoking in adults, with an hazard ratio (HR) of 1.43 (95% CI 0.97, 2.11). Ever-smokers who also had childhood passive smoking exposure had a higher risk of RA than smokers not exposed during childhood [HR 1.67 (95% CI 1.17, 2.39)], but without a significant difference (P = 0.30). RA began earlier in smokers exposed to childhood passive smoking. This study confirms that active smoking is associated with an increased risk of RA. It suggests for the first time that passive exposure to tobacco during childhood might also increase the risk of RA in future light smokers and probably non-smokers. Our results highlight the importance of avoiding any tobacco environment in children, especially in those with a family history of RA.

Synergy of environmental and genetic risk in RA.

Synergy of environmental and genetic risk in RA.

Estrogen induces St6gal1 expression and increases IgG sialylation in mice and patients with rheumatoid arthritis: a potential explanation for the increased risk of rheumatoid arthritis in postmenopausal women

BackgroundRheumatoid arthritis (RA) preferentially affects women, with the peak incidence coinciding with estrogen decrease in menopause. Estrogen (E2) may therefore have intrinsic immune-regulatory properties that vanish with menopause. Fc sialylation is a crucial factor determining the inflammatory effector function of antibodies. We therefore analyzed whether E2 affects immunoglobulin G (IgG) sialylation.MethodsPostmenopausal (ovariectomized) mice were immunized with ovalbumin and treated with E2 or vehicle. Total and ovalbumin-specific IgG concentrations, sialylation, and Fcγ receptor expression were analyzed. Postmenopausal women with RA receiving hormone replacement therapy, including E2, or no treatment were analyzed for IgG sialylation. Furthermore, effects of E2 on the expression of the sialylation enzyme β-galactoside α2,6-sialyltransferase 1 (St6Gal1) were studied in mouse and human antibody-producing cells.ResultsE2 treatment significantly increased Fc sialylation of total and ovalbumin-specific IgG in postmenopausal mice. Furthermore, E2 led to increased expression of inhibitory Fcγ receptor IIb on bone marrow leukocytes. Treatment with E2 also increased St6Gal1 expression in mouse and human antibody-producing cells, providing a mechanistic explanation for the increase in IgG-Fc sialylation. In postmenopausal women with RA, treatment with E2 significantly increased the Fc sialylation of IgG.ConclusionsE2 induces anti-inflammatory effector functions in IgG by inducing St6Gal1 expression in antibody-producing cells and by increasing Fc sialylation. These observations provide a mechanistic explanation for the increased risk of RA in conditions with low estrogen levels such as menopause.

CD4+ and B Lymphocyte Expression Quantitative Traits at Rheumatoid Arthritis Risk Loci in Patients With Untreated Early Arthritis: Implications for Causal Gene Identification.

ObjectiveRheumatoid arthritis (RA) is a genetically complex disease of immune dysregulation. This study sought to gain further insight into the genetic risk mechanisms of RA by conducting an expression quantitative trait locus (eQTL) analysis of confirmed genetic risk loci in CD4+ T cells and B cells from carefully phenotyped patients with early arthritis who were naive to therapeutic immunomodulation.Methods RNA and DNA were isolated from purified B and/or CD4+ T cells obtained from the peripheral blood of 344 patients with early arthritis. Genotyping and global gene expression measurements were carried out using Illumina BeadChip microarrays. Variants in linkage disequilibrium (LD) with non‐HLA RA single‐nucleotide polymorphisms (defined as r2 ≥ 0.8) were analyzed, seeking evidence of cis‐ or trans‐eQTLs according to whether the associated probes were or were not within 4 Mb of these LD blocks.ResultsGenes subject to cis‐eQTL effects that were common to both CD4+ and B lymphocytes at RA risk loci were FADS1,FADS2,BLK,FCRL3,ORMDL3,PPIL3, and GSDMB. In contrast, those acting on METTL21B,JAZF1,IKZF3, and PADI4 were unique to CD4+ lymphocytes, with the latter candidate risk gene being identified for the first time in this cell subset. B lymphocyte–specific eQTLs for SYNGR1 and CD83 were also found. At the 8p23 BLK–FAM167A locus, adjacent genes were subject to eQTLs whose activity differed markedly between cell types; in particular, the FAM167A effect displayed striking B lymphocyte specificity. No trans‐eQTLs approached experiment‐wide significance, and linear modeling did not identify a significant influence of biologic covariates on cis‐eQTL effect sizes.ConclusionThese findings further refine the understanding of candidate causal genes in RA pathogenesis, thus providing an important platform from which downstream functional studies, directed toward particular cell types, may be prioritized.

Regulation of the Cell Cycle and Inflammatory Arthritis by the Transcription Cofactor LBH Gene.

Rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) display unique aggressive behavior, invading the articular cartilage and promoting inflammation. Using an integrative analysis of RA risk alleles, the transcriptome and methylome in RA FLS, we recently identified the limb bud and heart development (LBH) gene as a key dysregulated gene in RA and other autoimmune diseases. Although some evidence suggests that LBH could modulate the cell cycle, the precise mechanism is unknown and its impact on inflammation in vivo has not been defined. Our cell cycle analysis studies show that LBH deficiency in FLS leads to S-phase arrest and failure to progress through the cell cycle. LBH-deficient FLS had increased DNA damage and reduced expression of the catalytic subunit of DNA polymerase α. Decreased DNA polymerase α was followed by checkpoint arrest due to phosphorylation of checkpoint kinase 1. Because DNA fragments can increase arthritis severity in preclinical models, we then explored the effect of LBH deficiency in the K/BxN serum transfer model. Lbh knockout exacerbated disease severity, which is associated with elevated levels of IL-1β and checkpoint kinase 1 phosphorylation. These studies indicate that LBH deficiency induces S-phase arrest that, in turn, exacerbates inflammation. Because LBH gene variants are associated with type I diabetes mellitus, systemic lupus erythematosus, RA, and celiac disease, these results suggest a general mechanism that could contribute to immune-mediated diseases.

Risk factors: Oral contraceptive use linked to lower risk of RA.

Risk factors: Oral contraceptive use linked to lower risk of RA.

Validation of the EULAR definition of arthralgia suspicious for progression to rheumatoid arthritis.

Recently a EULAR-taskforce defined arthralgia suspicious for progression to RA, in order to allow inclusion of homogeneous sets of arthralgia patients in clinical studies. This longitudinal study aimed (i) to validate this definition in arthralgia patients in whom rheumatologists felt that imminent RA was more likely than other arthralgias [clinically suspect arthralgia (CSA)], that is, the target population fulfilling the entry criterion, and (ii) to explore the performance in arthralgia patients who were referred to secondary care prior to rheumatological evaluation, hence ignoring the entry criterion. The definition was assessed in 241 Dutch patients identified with CSA by rheumatologists and 113 patients referred to the Umeå university hospital with recent-onset arthralgia in small joints. The external reference was arthritis development <2 years' follow-up. CSA patients with a positive definition (⩾3/7 parameters present) had an increased risk for developing arthritis compared with definition-negative CSA patients (hazard ratio = 2.1, 95% CI: 0.9, 4.7). The sensitivity was 84% and the positive predictive value 30%. In arthralgia patients in whom the definition was applied before rheumatological evaluation, a positive definition was neither sensitive (10%) nor predictive (positive predictive value 3%). The EULAR definition of arthralgia suspicious for progression to RA is sensitive when used to support the rheumatologist's opinion on imminent RA. This validation study shows that the definition, when used as designed, further homogenizes patients that rheumatologists consider at risk for RA. To arrive at a high specificity, the clinical definition needs to be combined with biomarkers.

Evaluation of the association of single nucleotide polymorphisms in DDP4 and CDK5RAP2 genes with rheumatoid arthritis susceptibility in Iranian population

BackgroundRheumatoid arthritis (RA) is known as a chronic autoimmune inflammatory disorder, which is characterized mainly by the progressive inflammation and destruction of the joints. In the pathogenesis of RA, a variety of cell types such as lymphocyte, dendritic cells, osteoclasts and synovial fibroblasts are involved. Genetic proneness has been implicated in the pathogenesis of RA. The aim of this study was to evaluate the association of single nucleotide polymorphisms (SNPs) in DPP4 and CDK5RAP2 genes and risk of RA in Iranian population. MethodsFor genotyping, 623 RA patients and 412 healthy subjects were recruited. Genetic analysis of DPP4 gene rs12617656 and CDK5RAP2 gene rs12379034 polymorphisms was conducted using TaqMan allelic discrimination (for rs12617656) and ARMS-PCR (for rs12379034) methods. ResultsExperiments demonstrated that alleles and genotypes of both SNPs were represented equally in RA patients and controls. Statistical analysis revealed that none of the rs12617656 and rs12379034SNPs had significant differences in prevalence of both alleles and genotypes between RA patients and healthy controls. ConclusionsIt appears that gene polymorphisms of DPP4 and CDK5RAP2 are not involved in the pathogenesis of RA in Iranian population.

Genetic and environmental risk factors for rheumatoid arthritis in a UK African ancestry population: the GENRA case-control study.

Objectives. To evaluate whether genetic and environmental factors associated with RA in European and Asian ancestry populations are also associated with RA in African ancestry individuals. Methods. A case–control study was undertaken in 197 RA cases and 868 controls of African ancestry (Black African, Black Caribbean or Black British ethnicity) from South London. Smoking and alcohol consumption data at RA diagnosis was captured. Genotyping was undertaken (Multi-Ethnic Genotyping Array) and human leukocyte antigen (HLA) alleles imputed. The following European/Asian RA susceptibility factors were tested: 99 genome-wide loci combined into a genetic risk score; HLA region [20 haplotypes; shared epitope (SE)]; smoking; and alcohol consumption. The SE was tested for its association with radiological erosions. Logistic regression models were used, including ancestry-informative principal components, to control for admixture. Results. European/Asian susceptibility loci were associated with RA in African ancestry individuals. The genetic risk score provided an odds ratio (OR) for RA of 1.53 (95% CI: 1.31, 1.79; P = 1.3 × 10 −7). HLA haplotype ORs in European and African ancestry individuals were highly correlated (r = 0.83, 95% CI: 0.56, 0.94; P = 1.1 × 10 −4). Ever-smoking increased (OR = 2.36, 95% CI: 1.46, 3.82; P = 4.6 × 10 −4) and drinking alcohol reduced (OR = 0.34, 95% CI: 0.20, 0.56; P = 2.7 × 10 −5) RA risk in African ancestry individuals. The SE was associated with erosions (OR = 2.61, 95% CI: 1.36, 5.01; P = 3.9 × 10 −3). Conclusion. Gene–environment RA risk factors identified in European/Asian ancestry populations are relevant in African ancestry individuals. As modern statistical methods facilitate analysing ancestrally diverse populations, future genetic studies should incorporate African ancestry individuals to ensure their implications for precision medicine are universally applicable.

Sedentary behaviour is associated with increased long-term cardiovascular risk in patients with rheumatoid arthritis independently of moderate-to-vigorous physical activity

BackgroundRheumatoid Arthritis (RA) is associated with an increased risk of cardiovascular disease (CVD). The physical dysfunction symptomatic of RA means people living with this disease spend large periods of the day sedentary, which may further elevate their risk of CVD. The primary aim of this study was to investigate relationships between objectively assessed sedentary behaviour patterns and light physical activity (LPA) with 10-year risk of CVD. Secondary aims were to explore the role of sedentary behaviour patterns and LPA for individual CVD risk factors and functional disability in RA. The extent to which associations were independent of moderate-to-vigorous physical activity (MVPA) engagement was also examined.MethodsBaseline data from a subsample of participants recruited to the Physical Activity in Rheumatoid Arthritis (PARA) study were used to answer current research questions. Sixty-one patients with RA (mean age (± SD) = 54.92 ± 12.39 years) provided a fasted blood sample and underwent physical assessments to evaluate factors associated with their cardiovascular health. Sedentary behaviour patterns (sedentary time, sedentary bouts, sedentary breaks), LPA and MVPA were measured via 7-days of accelerometry. Ten-year CVD risk was computed (Q-risk-score2), and functional disability determined via questionnaire.ResultsRegressions revealed significant positive associations between sedentary time and the number of sedentary bouts per day ≥20 min with 10-year CVD risk, with the reverse true for LPA participation. Associations were independent of MVPA engagement.ConclusionsPromoting LPA participation and restricting sedentary bouts to <20 min may attenuate long-term CVD risk in RA, independent of MVPA engagement.Trial registrationISRCTN04121489 (retrospectively registered 19/10/2012).