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The availability of Janus kinase (JAK) inhibitors has transformed the management of rheumatoid arthritis (RA), helping patients achieve clinical remission. However, the emergence of opportunistic infections (OIs) associated with the use of JAK inhibitors has been reported. This structured literature review was conducted to summarize reports of OIs associated with JAK inhibitor treatment for RA in clinical trials.Structured searches were performed in MEDLINE® and Embase® to identify relevant clinical trial data through March 2021. Bibliographic searches of recent reviews were also conducted, and gray literature searches were used to supplement key gap areas. Publications were screened, extracted, and quality assessed. Data were narratively synthesized.Following screening, 105 publications describing 62 unique clinical trials reporting the rates of OIs in RA patients treated with JAK inhibitors were included. Overall, the highest exposure-adjusted incidence rate was reported for herpes zoster (HZ) infection (any form), followed by OI (any) and tuberculosis based on limited data from clinical trials with approved doses of JAK inhibitors. Lack of head-to-head trials and differences in trial design preclude direct comparison across JAK inhibitors. Higher rates of OIs were noted in the Asian and Australian populations compared with the global population. Higher rates of OIs were also noted with increasing dose of JAK inhibitors in most clinical trial data.HZ was the most common OI reported among RA patients using all currently approved JAK inhibitors in clinical trials, although tuberculosis and other OIs were also reported. More long-term safety studies in the real-world setting are needed to compare the risk of OIs between various JAK inhibitors.

Background/Aims Tumour necrosis factor inhibitors (TNFi) have advanced the clinical management of rheumatoid arthritis (RA); however, only 30-40% of patients who receive initial treatment with a TNFi experience a beneficial response. The discovery of biomarkers of TNFi response would facilitate improved response rates and more objective monitoring of inflammation. Gene transcript levels measured in the blood of RA patients represent an attractive source of biomarkers. For example, a study by Oswald et al demonstrated reproducible changes in gene expression modules in RA patients treated effectively with a TNFi. Such gene modules were previously defined by Chaussabel et al following the assessment of gene co-expression patterns, transcript clustering patterns and functional associations amongst transcripts from several inflammatory diseases. We aim to replicate the changes in modular gene co-expression reported to occur in response to TNFi therapy in RA in a UK cohort described by Oswald et al; to test if changes in modular expression are specific to TNFi therapy by analysing change in gene co-expression in response to methotrexate (MTX); and to determine if module expression transitions towards a disease-free state in responding patients. Methods Published whole blood transcriptomic data from disease-free controls (n = 10) and RA patients treated with either the TNFi adalimumab (n = 70) or MTX (n = 85) were studied. Transcriptomic data were available at pre-treatment and at 3-months (TNFi) and 4-weeks (MTX) post-treatment. Response to treatment was assessed using the EULAR response criteria following 3/6-months on-drug. For each of the 27 modules, the fraction of probes that significantly (p < 0.05) changed in expression between time-points was recorded. Linear mixed models were used to test if module expression transitioned towards a disease-free state following treatment. Results In the TNFi cohort, 25 of the 27 modules significantly changed in expression between pre- and post-treatment, replicating published findings by Oswald et al. Six of these 27 modules transitioned towards a disease-free state by 3-months. Transition in module expression was irrespective of treatment response in 5 of the 6 modules, however one module (module 3.2) appeared to be dependent on good response to adalimumab. This module was linked to pathways of inflammation and TNF signalling. Similar patterns of modular expression changes were observed in the MTX cohort, but with reduced significance compared to TNFi treated patients. Conclusion This study provides independent replication of changes in modular gene expression in TNFi treated RA patients. Gene expression changes were observed regardless of treatment response and were not specific to TNFi therapy. These results suggest that some factors of biological response are not detected by clinical classifiers of treatment response. Further research is now needed to test the utility of gene modules for prediction of clinical response, or for objective monitoring of molecular pathways that are responsive to treatment. Disclosure M.A. Sutcliffe: None. N. Nair: None. J. Oliver: None. A. Morgan: None. J. Isaacs: None. G. Wilson: None. S. Verstappen: None. S. Viatte: None. K. Hyrich: None. A. Morris: None. A. Barton: None. D. Plant: None.

Background/Aims The treatment of rheumatoid arthritis (RA) has improved since the introduction of targeted biological disease-modifying antirheumatic drugs (bDMARDs), such as adalimumab. However, no treatment options for RA are universally effective. Psychological factors may have an important role in treatment response. Published data reported that pre-treatment psychological variables such as an increased treatment necessity belief correlated with better adherence to adalimumab in RA patients. This current study aimed to investigate whether psychological factors correlate with change in 4V-DAS28-CRP as well as subcomponents of the score in adalimumab-treated RA patients. Methods Psychological, clinical and demographic data and DAS28 scores were collected pre-treatment, and at 3,6, and 12-months post-treatment, as part of a prospective national study, BRAGGSS. Sixteen pre-treatment clinical and psychological variables were tested for association with treatment response at 3 and 12 months. Multiple linear regression models were analysed and a Bonferroni corrected p-value of < 0.003 was applied at each interval to assess significance. Results Data was available for 501 patients at 3 months follow up. Pre-treatment Beliefs about Medicine Questionnaire (BMQ) scores with regards to treatment necessity (P = 0.001), and two domains of the Illness Perception Questionnaire (IPQ), which were treatment belief and treatment control (P = 0.0001), correlated with the change in DAS28 by 3 months (Table 1). At 12 months, data were available for 362 patients. The treatment belief domain of the pre-treatment Illness Perception Questionnaire correlated with the change in tender joint count (P = 0.001) (Table 1). At 12 months no other sub-components correlated with the psychological variables. Conclusion Pre-treatment scores with regards to Illness Perception and Beliefs about Medicine correlated with 4V-DAS28-CRP response at 3 months. Of the subcomponents of DAS28, the psychological variables showed the highest correlation with tender joint count; as the tender joint count receives the highest weighting in the 4 variable DAS28 score, this may confound the assessment of treatment response. It will be necessary to undertake further analyses to assess the predictive value of these potentially modifiable psychological variables identified, but to also understand factors contributing to these psychological scores, such as the role of severe disease itself on psychological beliefs. Disclosure N. Raza: None. N. Nair: None. D. Plant: None. K. Hyrich: None. A.W. Morgan: None. J. Isaacs: None. A.G. Wilson: None. A. Barton: None.

Background/Aims Control of disease activity in Rheumatoid Arthritis (RA) is crucial to prevent long-term joint damage and disability. European Alliance of Associations for Rheumatology (EULAR) guidelines recommend focus on disease activity when measuring health outcomes in people living with RA. Particularly, one of their four overarching principles targets clinical remission, defined as the absence of significant inflammatory disease activity, or low disease activity an acceptable alternative. In EULAR’s most recent guidelines (2014), attention was drawn to the role of comorbidities in RA disease management noting the “potential to preclude treatment intensification”. Besides this, recent work by the EULAR Task Force on difficult-to-treat RA recognises that comorbidities can influence the assessment of inflammatory activity in individuals with RA. This study aimed to identify early predictors of poor disease activity at five and 10 years, focussing on comorbidities alongside clinical/sociodemographic factors at first presentation. Methods Patients were recruited from two UK-based RA cohorts; Early Rheumatoid Arthritis Study (ERAS, 1986-2001) and Early Rheumatoid Arthritis Network (ERAN, 2002-2012). Participants were classified into two groups; low ( Results 2,701 patients with RA were recruited (mean age 56.1 years, 66.9% female); 5-year follow-up data were available for 1,718 (63.4%) and 10-year for 820 (30.4%) patients. A higher proportion of individuals had DAS28≥3.2 values at 10 years than five (65.6% vs 59.7%). In multivariable analyses, baseline RDCI was not associated with DAS28 at five (OR 1.05, 95% CI 0.91 to 1.22) or 10 years (OR 0.99, 95% CI 0.75 to 1.31). Sociodemographic factors (female gender, worse deprivation) and poorer baseline HAQ were associated with DAS28≥3.2 at both timepoints, with no association found with age at onset. Being seropositive was associated with DAS28≥3.2 at 5 but not 10 years of follow-up. Conversely, a relationship existed between presence of erosions at baseline and 10-year DAS28 (OR 1.82, 95% CI 1.16 to 2.85). Conclusion This study found no association between baseline comorbidity burden and long-term RA disease activity. However, in models adjusted for comorbidity burden, associations with sociodemographic and clinical factors were demonstrated. These results build upon those relating to functional outcome and will accelerate the identification of those RA patients at increased risk of worse outcomes at initial rheumatology appointment. Additionally, these findings suggest that tailored intervention can be implemented in a timely manner, in line with national and international recommendations, potentially limiting permanent joint damage and disability to improve quality of life for individuals with RA. Disclosure A.D. Busby: None. J. Wason: None. A.G. Pratt: None. A. Young: None. J. Isaacs: None. E. Nikiphorou: None.

Physical and mental illnesses are driven by ethnicity, social, environmental and economic determinants. Novel theoretical frameworks in rheumatoid arthritis (RA) focus on links and adverse interactions between and within biological and social factors. This review aimed to summarise associations between socioeconomic status (SES) and RA disease activity, and implications for future research. Articles studying the association between SES and RA disease activity were identified, from 1946 until March 2021. The research question was: Is there an association between social deprivation and disease activity in people with RA? Articles meeting inclusion criteria were examined by one author, with 10% screened at abstract and full paper stage by a second author. Disagreements were resolved with input from a third reviewer. Information was extracted on definition/measure of SES, ethnicity, education, employment, comorbidities, disease activity and presence/absence of association between SES and disease activity. Initially, 1750 articles were identified, with 30 articles ultimately included. SES definition varied markedly—10 articles used a formal scale and most used educational attainment as a proxy. Most studies controlled for lifestyle factors including smoking and body mass index, and comorbidities. Twenty-five articles concluded an association between SES and RA disease activity; two were unclear; three found no association. We have demonstrated the association between low SES and worse RA outcomes. There is a need for further research into the mechanisms underpinning this, including application of mixed-methods methodology and consideration of syndemic frameworks to understand bio–bio and bio–social interactions, to examine disease drivers and outcomes holistically.

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.

Biologic therapy for treatment of rheumatoid arthritis (RA) has evolved considerably over the past 20 years. Biosimilar development continues to accelerate at a frenetic pace worldwide. Initial regulatory efforts were developed within the EU and subsequent guidelines have now evolved in over 20 countries. Biosimilars by definition are highly similar, with ‘comparable quality, safety, and efficacy’ (EMA) and ‘no clinically meaningful differences in safety, purity, and potency’ (FDA) to the reference product. Development and manufacturing are based on reverse engineering of the reference product as only the primary amino acid sequence is known. Testing of primary, secondary, tertiary, and quaternary structure, binding pharmacokinetics, and stability is required. Characterization of post-translational modifications and biologic function, pharmacokinetics, evaluation of immunogenicity, and at least one comparative efficacy clinical trial are major requirements for regulatory approval. Clinical trials to assess biosimilarity are required in only one clinical indication and may be extrapolated to other indications for which the reference product is approved. Both single and multiple switching trials (between biosimilar and reference product) have yielded consistent results across numerous patient populations and diseases, with no evidence of detrimental outcomes. Two prospective large observational series (Danbio and Nor-Switch) have similarly assessed non-medical switching. Several open-label switching studies have revealed equivalent efficacy, safety, and discontinuation rates but real-world studies have raised concerns about potential nocebo responses.

Immunogenicity, or the formation of antidrug antibodies (ADAbs), has been described in response to all biologic therapies licensed for rheumatoid arthritis (RA). In patients treated with monoclonal antibodies, immunogenicity may be associated with low serum drug levels, loss of therapeutic response, poor drug survival, and/or adverse events such as infusion reactions. In this chapter we review the factors that may predispose to immunogenicity to biologics as well as mitigating factors in RA such as the effect of concomitant non-biologic disease-modifying antirheumatic drugs (DMARDs). The reported incidence of ADAbs varies greatly depending on techniques used for measurement. The interpretation of these is discussed followed by the effect of antidrug antibodies and drug levels on drug efficacy and safety of biologics in RA. Finally, we evaluate the evidence to date on the impact of biosimilar switching on immunogenicity and tolerizing to ADAbs.

Purpose This retrospective study evaluates the effectiveness and safety of the Angio-Seal closure device in superficial femoral artery (SFA) antegrade punctures compared to common femoral artery (CFA) antegrade punctures. Methods Over a period of 46 months from January 2012, consecutive patients who underwent antegrade CFA or SFA punctures using Angio-Seal as a closure device in a single centre were studied. Patients were identified by reading all the individual reports on our radiology system for all patients who underwent any angiographic examination during the study period, and their individual case notes were subsequently reviewed. A retrospective analysis of prospectively collected data on patients' demographics, type of intervention, clinical indication, Angio-Seal size, haemostasis status and complications was performed. Results Overall, 194 patients (mean (s.d.) age 74(12) years, 123(44%) males) underwent CFA or SFA antegrade punctures. A total of 228 (CFA group, n = 70, SFA group, n = 158) antegrade punctures were performed. Clinical characteristics of the two groups were comparable. Angio-Seal size 6F was deployed in 69(99%) antegrade CFA punctures and 155(98%) antegrade SFA punctures (P = 1.000). Haemostasis was achieved in 65(93%) antegrade CFA punctures compared to 156(99%) antegrade SFA punctures (P = 0.030). Conclusion Angio-Seal closure device is safe and effective method of haemostasis both in antegrade SFA and CFA punctures with no significant complications or delayed discharge.

Rheumatoid arthritis (RA) is characterised by chronic synovial joint inflammation. Treatment has been revolutionised by tumour necrosis factor alpha inhibitors (TNFi) but each available drug shows a significant non-response rate. We conducted a genome-wide association study of 1752 UK RA TNFi-treated patients to identify predictors of change in the Disease Activity Score 28 (DAS28) and subcomponents over 3-6 months. The rs7195994 variant at the FTO gene locus was associated with infliximab response when looking at a change in the swollen joint count (SJC28) subcomponent (p = 9.74 × 10

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterised by joint inflammation. Studies in mice and patients suffering from autoimmune diseases described a novel subset of B cells named age-associated B cells (ABCs). Moreover, a subset of synovial fluid B cells with a similar phenotype and FcRL4 expression contributes to RA pathogenesis. Newly diagnosed patients were recruited from the Newcastle Early Arthritis Clinic. B cell subsets in blood were phenotyped using flow cytometry. NanoString Immunlogy Panel was used to asses gene expression from sorted ABCs, naïve, memory and CD5+ B cells from RA patients, age-matched healthy controls and disease controls. Our work showed that there are no significant differences in the frequency of ABCs between RA patients, and disease and healthy controls. Our results also show that ABCs resemble the memory B cell phenotype regarding class-switch immunoglobulins expression. Interestingly, the FcRL4+, the Ki67+ and the T-bet expressing B cells were enriched in the ABC population. ABCs expressed high levels of HLA-DR and co-stimulatory molecules, as well as the activation marker, CD69. Gene expression analysis showed a specific gene signature for the ABCs when compared to the other B cells. KEGG analysis results showed that differentially expressed genes were enriched in the antigen presentation and the cytokine-cytokine receptor interaction pathways. Moreover, 13 genes were overexpressed in ABCs from the RA patients compared to the other control groups. This data supports the idea that ABCs have a pathogenic role in RA, potentially via T cell stimulation and migration to sites of inflammation. However, further characterisation of this subset and functional studies are needed.

Eligibility for anti-tumour necrosis factor (TNF) therapy in most European countries is restricted to severe, active rheumatoid arthritis (RA). The DAS28 score is a marker of disease severity and incorporates one of two inflammatory markers, erythrocyte sedimentation rate (ESR) or C-reactive protein. We aimed to determine the relation between genetic variants known to affect ESR and levels of ESR in patients with active RA. DNA samples were genotyped for four single-nucleotide polymorphisms (SNPs) rs7527798 (CR1L), rs6691117 (CR1), rs10903129 (TMEM57) and rs1043879 (C1orf63). The association between SNPs and baseline ESR, baseline DAS28-ESR, and change in DAS28-ESR was evaluated. Baseline ESR was significantly associated with CR1 rs6691117 genotype (P=0.01). No correlation was identified between baseline DAS28-ESR or change in DAS28-ESR. In conclusion, genetic variation in the gene encoding CR1 may alter ESR levels but not DAS28-ESR, indicating no adjustment for CR1 genotype is required in the assessment of patients with severe active RA.

Aim: A genetic variant has recently reached genome-wide significance for association with TNF-inhibitor response in rheumatoid arthritis patients. Here we undertake a replication study in a UK Caucasian population to test for association with TNF-inhibitor response. Materials & methods: The genetic variant, rs3794271, located within the PDE3A–SLCO1C1 locus was analyzed for correlation with treatment response using both the EULAR classification criteria and absolute change in (Δ)DAS28 scores as outcome measures. Results: Genotype data were available from 1750 TNF-inhibitor treated individuals. However, no evidence for association was observed (EULAR: p = 0.91 and ΔDAS28: p = 0.93). Furthermore, no significant associations were observed upon stratification by the anti-TNF received (p > 0.05). Conclusion: In the largest replication cohort conducted to date, no evidence for association was observed.

Up to 40% of patients with rheumatoid arthritis treated with anti-tumour necrosis factor (TNF) drugs do not respond because of primary inefficacy or loss of response. Although one explanation is that immunogenicity leads to the development of anti-drug antibodies and low drug concentrations, the clinical usefulness of pharmacological monitoring is debated. Our aim was to assess whether the presence of anti-drug antibodies and non-trough drug concentrations could predict treatment response in patients with rheumatoid arthritis treated with anti-TNF drugs.331 patients were selected from a multicentre prospective cohort (160 treated with adalimumab, 171 etanercept). Serum samples were collected at 3, 6, and 12 months after treatment initiation. Anti-drug antibodies were measured with RIA, drug concentrations with ELISAs, and Disease Activity Score in 28 joints (DAS28) at each timepoint. Linear and logistic regression, generalised estimating equation (GEE), and receiver operating characteristic curves were used to test the association and predictive value of anti-drug antibodies and non-trough drug concentrations on treatment response (ΔDAS28).835 serial samples were tested (414 adalimumab, 421 etanercept). Anti-adalimumab antibodies were detected in 31 (24·8%) of 125 patients who had completed 12 month follow-up and none of the etanercept patients. The presence of anti-drug antibodies was associated with lower adalimumab concentrations (Spearman r=-0·66, p=0·0041). At 3 months, anti-drug antibody formation and low adalimumab concentrations were significant predictors of poor treatment response at 12 months (area under curve [AUC] 0·68, 95% CI 0·54-0·81, and 0·66, 0·55-0·77, respectively; and both combined 0·71, 0·57-0·85). Adalimumab concentration was the most significant independent predictor of ΔDAS28 after adjustment for confounders (regression coefficient 0·12, 95% CI 0·06-0·18; p=0·003). High etanercept concentrations were associated with better treatment response (p=0·01), but low concentrations at 3 months were not a significant predictor of poor treatment response at 12 months (AUC 0·58, 95% CI 0·46-0·70). In the combined GEE model including adalimumab and etanercept, a body-mass index of 30 kg/m(2) or more was associated with low drug concentrations (regression coefficient 0·78, 95% CI 0·37-1·18; p0·0001).Pharmacological testing in anti-TNF initiated patients is clinically useful even in the absence of trough levels. At 3 months, presence of anti-drug antibodies and low adalimumab concentrations are a significant predictor for poor treatment response at 12 months. Strengths of this study include a large, prospective cohort and use of RIA to measure antibodies (less prone to drug interference). Although non-trough concentrations might have underestimated the frequency of antibodies, their presence still predicted response.MJ is a MRC Clinical Training Fellow supported by the North West England Medical Research Council Fellowship Scheme in Clinical Pharmacology and Therapeutics, which is funded by the UK Medical Research Council (grant number G1000417/94909), ICON, GlaxoSmithKline, AstraZeneca, and the Medical Evaluation Unit. Arthritis Research UK (grant ref 20385).

Introduction Primary biliary cirrhosis (PBC) is an autoimmune liver disease with approximately 50% of patients experiencing fatigue. This can be a particularly debilitating symptom, affecting quality of life and resulting in social isolation. Fatigue is highlighted by patients as a priority for research and patient support groups were involved in designing this trial. This is the first randomised controlled trial to investigate a treatment for fatigue in PBC. The trial protocol is innovative as it utilises novel magnetic resonance spectroscopy (MRS) techniques as an outcome measure. The protocol will be valuable to research groups planning clinical trials targeting fatigue in PBC and also transferrable to other conditions associated with fatigue. Methods and analysis RITPBC is a Medical Research Council (MRC) and National Institute for Health Research (NIHR) Efficacy and Mechanism Evaluation Programme (EME)-funded project. It is a phase II, single-centre, randomised controlled, double-blinded trial comparing rituximab with placebo in fatigued PBC patients. 78 patients with PBC and moderate to severe fatigue will be randomised to receive two infusions of rituximab or placebo. The study aims to assess whether rituximab improves fatigue in patients with PBC, the safety, and tolerability of rituximab in PBC and the sustainability of any beneficial actions. The primary outcome will be an improvement in fatigue domain score of the PBC-40, a disease-specific quality of life measure, evaluated at 12-week assessment. Secondary outcome measures include novel MRS techniques assessing muscle bioenergetic function, physical activity, anaerobic threshold and symptom, and quality of life measures. The trial started recruiting in October 2012 and recruitment is ongoing. Ethics and dissemination The trial has ethical approval from the NRES Committee North East, has Clinical Trial Authorisation from MHRA and local R&D approval. Trial results will be communicated to participants, presented at national and international meetings and published in peer-reviewed journals. Trial registration number ISRCTN03978701.

Appendicitis is a common cause of acute abdominal pain in children and is treated by an open or laparoscopic appendicectomy. Well documented post-operative complications include wound infection, intra-abdominal collection, and adhesional bowel obstruction. We present the rare case of right sacro-iliitis and iliac bone osteomyelitis in a 13 year old boy following an open appendicectomy for a perforated appendicitis.

Govorimo o politikama europskih zemalja uspoređujući podatake i situacije. No, mi jasno znamo gdje želimo ići. Želimo narednim generacijama osigurati svijet koji je više ‘prijateljski’, bliži i usmjeren na ukupnu dobrobit djece i njezinih građana.

Approximately 30% of rheumatoid arthritis (RA) patients fail to respond to anti-tumour necrosis factor (anti-TNF) treatment;1 hence, the ability to predict which patients will respond to treatment would represent a major clinical advance. Vitamin D has been implicated in many autoimmune diseases including RA; in addition, vitamin D has been shown to induce TNFα production by some immune cells leading to the hypothesis that vitamin D levels may influence anti-TNF treatment response.2 ,3 Several studies have now confirmed the association of genetic variants within four vitamin D metabolism genes ( GC, DHCR7/NADSYN1, CYP2R1, CYP24A1 ) with circulating vitamin D levels in healthy controls.4 ,5 In addition, single nucleotide polymorphisms (SNPs) in these genes have also been associated with autoimmune diseases.6 The association of the same variants in the same genes that control circulating levels of vitamin D with response to anti-TNF treatment provides an unbiased test of the hypothesis that vitamin D levels are important in response to these therapies (Mendelian randomisation).7 We, therefore, investigated the effect of vitamin D on response to anti-TNF therapy, testing six SNPs previously associated with circulating levels of vitamin D4 ,5 for association with response to anti-TNF therapy in RA patients from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS) cohort (table 1), which includes patients recruited across the UK.8 SNPs were selected to capture by linkage disequilibrium (LD) (r2>0.8) 94.26% of SNPs previously associated with vitamin D levels in two previous studies.4 ,5 Multivariate linear and logistic regression was used to assess the effects of each SNP on treatment response measured by absolute change in Disease Activity Score in 28 joints (DAS28) over 6 months9 (n=1396) or in poor (n=237) versus good (n=322) responders according to European League …

If a half-trillion dollar military budget lands on Capitol Hill and no one seems to hear, does it make a sound? You bet.

BACKGROUND: Recent genome-wide association studies (GWAS) have identified novel loci associated with sudden cardiac death (SCD). Despite this progress, identified DNA variants account for a relatively small portion of overall SCD risk, suggesting that additional loci contributing to SCD susceptibility await discovery. The objective of this study was to identify novel DNA variation associated with SCD in the context of coronary artery disease (CAD).METHODS AND FINDINGS: Using the MetaboChip custom array we conducted a case-control association analysis of 119,117 SNPs in 948 SCD cases (with underlying CAD) from the Oregon Sudden Unexpected Death Study (Oregon-SUDS) and 3,050 controls with CAD from the Wellcome Trust Case-Control Consortium (WTCCC). Two newly identified loci were significantly associated with increased risk of SCD after correction for multiple comparisons at: rs6730157 in the RAB3GAP1 gene on chromosome 2 (P = 4.93×10(-12), OR = 1.60) and rs2077316 in the ZNF365 gene on chromosome 10 (P = 3.64×10(-8), OR = 2.41).CONCLUSIONS: Our findings suggest that RAB3GAP1 and ZNF365 are relevant candidate genes for SCD and will contribute to the mechanistic understanding of SCD susceptibility.