Juvenile idiopathic arthritis polygenic risk scores are associated with cardiovascular phenotypes in early adulthood: a phenome-wide association study

Background: There is growing concern about the long-term cardiovascular health of patients with juvenile idiopathic arthritis (JIA). In this study we assessed the association between JIA polygenic risk and cardiovascular phenotypes (cardiovascular risk factors, early atherosclerosis/arteriosclerosis markers, and cardiac structure and function measures) early in life. Methods: JIA polygenic risk scores (PRSs) were constructed for 2,815 participants from the Avon Longitudinal Study of Parents and Children, using the single nucleotide polymorphism (SNP) weights from the most recent JIA genome wide association study. The association between JIA PRSs and cardiovascular phenotypes at age 24 years was assessed using linear and logistic regression. For outcomes with strong evidence of association, further analysis was undertaken to examine how early in life (from age seven onwards) these associations manifest. Results: The JIA PRS was associated with diastolic blood pressure (β 0.062, 95% CI 0.026 to 0.099, P = 0.001), insulin (β 0.050, 95% CI 0.011 to 0.090, P = 0.013), insulin resistance index (HOMA2_IR, β 0.054, 95% CI 0.014 to 0.095, P = 0.009), log hsCRP (β 0.053, 95% CI 0.011 to 0.095, P = 0.014), waist circumference (β 0.041, 95% CI 0.007 to 0.075, P = 0.017), fat mass index (β 0.049, 95% CI 0.016 to 0.083, P = 0.004) and body mass index (β 0.046, 95% CI 0.011 to 0.081, P = 0.010). For anthropometric measures and diastolic blood pressure, there was suggestive evidence of association with JIA PRS from age seven years. The findings were consistent across multiple sensitivity analyses. Conclusions: Genetic liability to JIA is associated with multiple cardiovascular risk factors, supporting the hypothesis of increased cardiovascular risk in JIA. Our findings suggest that cardiovascular risk is a core feature of JIA, rather than secondary to the disease activity/treatment, and that cardiovascular risk counselling should form part of patient care

State anxiety and emotional face recognition in healthy volunteers

High trait anxiety has been associated with detriments in emotional face processing. By contrast, relatively little is known about the effects of state anxiety on emotional face processing. We investigated the effects of state anxiety on recognition of emotional expressions (anger, sadness, surprise, disgust, fear and happiness) experimentally, using the 7.5% carbon dioxide (CO2) model to induce state anxiety, and in a large observational study. The experimental studies indicated reduced global (rather than emotion-specific) emotion recognition accuracy and increased interpretation bias (a tendency to perceive anger over happiness) when state anxiety was heightened. The observational study confirmed that higher state anxiety is associated with poorer emotion recognition, and indicated that negative effects of trait anxiety are negated when controlling for state anxiety, suggesting a mediating effect of state anxiety. These findings may have implications for anxiety disorders, which are characterized by increased frequency, intensity or duration of state anxious episodes

Nicotine preloading for smoking cessation: the Preloading RCT

Background: Nicotine preloading means using nicotine replacement therapy prior to a quit date while smoking normally. The aim is to reduce the drive to smoke, thereby reducing cravings for smoking after quit day, which are the main cause of early relapse. A prior systematic review showed inconclusive and heterogeneous evidence that preloading was effective and little evidence of the mechanism of action, with no cost-effectiveness data. Objectives: To assess (1) the effectiveness, safety and tolerability of nicotine preloading in a routine NHS setting relative to usual care, (2) the mechanisms of the action of preloading and (3) the cost-effectiveness of preloading. Design: Open-label randomised controlled trial with examination of mediation and a cost-effectiveness analysis. Setting: NHS smoking cessation clinics. Participants: People seeking help to stop smoking. Interventions: Nicotine preloading comprised wearing a 21 mg/24 hour nicotine patch for 4 weeks prior to quit date. In addition, minimal behavioural support was provided to explain the intervention rationale and to support adherence. In the comparator group, participants received equivalent behavioural support. Randomisation was stratified by centre and concealed from investigators. Main outcome measures: The primary outcome was 6-month prolonged abstinence assessed using the Russell Standard. The secondary outcomes were 4-week and 12-month abstinence. Adverse events (AEs) were assessed from baseline to 1 week after quit day. In a planned analysis, we adjusted for the use of varenicline (Champix®; Pfizer Inc., New York, NY, USA) as post-cessation medication. Cost-effectiveness analysis took a health-service perspective. The within-trial analysis assessed health-service costs during the 13 months of trial enrolment relative to the previous 6 months comparing trial arms. The base case was based on multiple imputation for missing cost data. We modelled long-term health outcomes of smoking-related diseases using the European-study on Quantifying Utility of Investment in Protection from Tobacco (EQUIPT) model. Results: In total, 1792 people were eligible and were enrolled in the study, with 893 randomised to the control group and 899 randomised to the intervention group. In the intervention group, 49 (5.5%) people discontinued preloading prematurely and most others used it daily. The primary outcome, biochemically validated 6-month abstinence, was achieved by 157 (17.5%) people in the intervention group and 129 (14.4%) people in the control group, a difference of 3.02 percentage points [95% confidence interval (CI) –0.37 to 6.41 percentage points; odds ratio (OR) 1.25, 95% CI 0.97 to 1.62; p = 0.081]. Adjusted for use of post-quit day varenicline, the OR was 1.34 (95% CI 1.03 to 1.73; p = 0.028). Secondary abstinence outcomes were similar. The OR for the occurrence of serious AEs was 1.12 (95% CI 0.42 to 3.03). Moderate-severity nausea occurred in an additional 4% of the preloading group compared with the control group. There was evidence that reduced urges to smoke and reduced smoke inhalation mediated the effect of preloading on abstinence. The incremental cost-effectiveness ratio at the 6-month follow-up for preloading relative to control was £710 (95% CI –£13,674 to £23,205), but preloading was dominant at 12 months and in the long term, with an 80% probability that it is cost saving. Limitations: The open-label design could partially account for the mediation results. Outcome assessment could not be blinded but was biochemically verified. Conclusions: Use of nicotine-patch preloading for 4 weeks prior to attempting to stop smoking can increase the proportion of people who stop successfully, but its benefit is undermined because it reduces the use of varenicline after preloading. If this latter effect could be overcome, then nicotine preloading appears to improve health and reduce health-service costs in the long term. Future work should determine how to ensure that people using nicotine preloading opt to use varenicline as cessation medication. Trial registration: Current Controlled Trials ISRCTN33031001.NIHR Health Technology Assessment programm

Additional file 2 of Juvenile idiopathic arthritis polygenic risk scores are associated with cardiovascular phenotypes in early adulthood: a phenome-wide association study

Additional file 2: Supplementary Table 1. Number of SNPs included in each JIA PRS generated using different SNP P value thresholds. Supplementary Table 2. SNPs included in the JIA PRS with the SNP P value threshold of <1.00E-5. SE, standard error; SNP, single nucleotide polymorphism. Supplementary Table 3. Data inclusion and data losses for the ALSPAC cohort and associated cardiovascular phenotypes. Outlying data was defined as those greater than three times the interquartile range. To maintain data anonymity, any cell containing a value less than 5 (including 0) has been replaced with <5. Apo-AI, apolioprotein-AI; Apo-B, apolipoprotein-B; BMI, body mass index; BP, Blood pressure; cIMT, carotid intima-media thickness; hsCRP, high sensitivity C-reactive protein; FMI, fat mass index; HOMA2_IR, Homeostasis Model Assessment 2 insulin reistance index; HDL, high density lipoprotein cholesterol; LDL, low density lipoprotein cholesterol; LVMI, left ventricular mass index. Supplementary Table 4. Assocations between JIA PRS generated using SNPs with the P value <5e-5, and positive and negative control outcomes. Pseudo R2 is used to evaulate the gooness of fit. CI, confidence interval; JIA, JIA; OR, odds ratio; PRS, polygenic risk score. Supplementary Table 5. Assocations between JIA PRS generated using SNPs with the P value <5e-5 and continous cardiovascular outcomes. *adjusted for 10 ancestry informed principal components and sex. Outcomes with P<0.05 are italicised. R2 is the proportion of the variance in the outcome which can be explained by the JIA PRS. Apo-AI, apolioprotein-AI; Apo-B, apolipoprotein-B; BMI, body mass index; BP, Blood pressure; CI, confidence interval; cIMT, carotid intima-media thickness; hsCRP, high sensitivity C-reactive protein; FMI, fat mass index; HOMA2_IR, Homeostasis Model Assessment 2 insulin reistance index; HDL, high density lipoprotein cholesterol; JIA, juvenile idiopathic arthritis; LDL, low density lipoprotein cholesterol; LVMI, left ventricular mass index; PRS, polygenic risk score. Supplementary Table 6. Assocations between JIA PRS generated using SNPs with the P value <5e-5 and dichotomous cardiovascular outcomes. *adjusted for 10 ancestry informed principal components and sex. Outcomes with P<0.05 are italicised. Pseudo R2 is used to evaulate the gooness of fit. BP, blood pressure; CI, confidence interval; JIA, juvenile idiopathic arthritis; OR, odds ratio. Supplementary Table 7. Assocations between JIA PRS generated using SNPs with the P value <1e-5 and cardiovascular outcomes in the main analysis, sensitivity analysis 1 (exclusion of MHSCregion SNP) and sensitivity analysis 2 (exclusion of participants with autoimmune disease). All estimates are adjusted for 10 ancestry informed principal components and sex. Outcomes with P <0.05 are italicised. *For dichotomous outcomes, OR (95% CI) are reported. R2 is the proportion of the variance in the outcome which can be explained by the JIA PRS. ^for dichotomous outcomes, pseudo R2 is reported. Pseudo R2 is used to evaulate the gooness of fit. Apo-AI, apolioprotein-AI; Apo-B, apolipoprotein-B; BMI, body mass index; BP, Blood pressure; CI, confidence interval; cIMT, carotid intima-media thickness; hsCRP, high sensitivity C-reactive protein; FMI, fat mass index; HOMA2_IR, Homeostasis Model Assessment 2 insulin reistance index; HDL, high density lipoprotein cholesterol; JIA, juvenile idiopathic arthritis; LDL, low density lipoprotein cholesterol; LVMI, left ventricular mass index; PRS, polygenic risk score. Supplementary Table 8. Assocations between JIA PRS generated using SNPs with the P value <5e-5 and cardiovascular outcomes from age 7 years to age 24 years for participants who attended the Focus24+ clinic. ^For measures which are not continuous N (%) is reported and participants with missing data are excluded from the denominator. *variable not calculated for earlier time points due to the different clinical thresholds by age. Apo-AI, apolioprotein-AI; Apo-B, apolipoprotein-B; BMI, body mass index; BP, Blood pressure; cIMT, carotid intima-media thickness; hsCRP, high sensitivity C-reactive protein; FMI, fat mass index; HOMA2_IR, Homeostasis Model Assessment 2 insulin reistance index; HDL, high density lipoprotein cholesterol; LDL, low density lipoprotein cholesterol; LVMI, left ventricular mass index. Supplementary Table 9. Assocations between JIA PRS generated using SNPs with the P value <5e-5 and cardiovascular outcomes from age 7 years to age 24 years. *adjusted for 10 ancestry informed principal components and sex. Outcomes with P<0.05 are italicised. R2 is the proportion of the variance in the outcome which can be explained by the JIA PRS. BMI, body mass index; BP, Blood pressure; CI, confidence interval; hsCRP, high sensitivity C-reactive protein; FMI, fat mass index; HOMA2_IR, Homeostasis Model Assessment 2 insulin reistance index; IA, juvenile idiopathic arthritis; PRS, polygenic risk score. Supplementary Table 10. Assocations between JIA PRS generated using SNPs with the P value <5e-5 and cardiovascular outcomes from age 7 years to age 24 years for Focus24+ participants who attended a) any earlier clinic and b) every earlier clinic. All estiamtes are adjusted for 10 ancestry informed principal components and sex. R2 is the proportion of the variance in the outcome which can be explained by the JIA PRS. Sample size varies by outcome due to missing data. BMI, body mass index; BP, Blood pressure; CI, confidence interval; hsCRP, high sensitivity C-reactive protein; FMI, fat mass index; HOMA2_IR, Homeostasis Model Assessment 2 insulin reistance index; IA, juvenile idiopathic arthritis; PRS, polygenic risk score

Livelihood and disadvantage

Guy Barnett, Helen Berry, Peter Tait, Aysha Fleming, Scott Hanson-Easey, Grant Blashki, Amanda Davies, Ning Ding, Aharon Factor, Brad Farrant, Donna Green, Jamie Hosking, Anna Lyth, Alexana Macmillan, Janie Maxwel

Supplementary Table S1 from State anxiety and emotional face recognition in healthy volunteers

Post-hoc paired-sample t-test results of hit data from studies one and tw