Different genes may be involved in distal and local sensitization: A genome-wide gene-based association study and meta-analysis.

BACKGROUND: Neuropathic pain symptoms and signs of increased pain sensitization in osteoarthritis (OA) patients may explain persistent pain after total joint replacement (TJR). Therefore, identifying genetic markers associated with pain sensitization and neuropathic-like pain phenotypes could be clinically important in identifying targets for early intervention. METHODS: We performed a genome-wide gene-based association study (GWGAS) using pressure pain detection thresholds (PPTs) from distal pain-free sites (anterior tibia), a measure of distal sensitization, and from proximal pain-affected sites (lateral joint line), a measure of local sensitization, in 320 knee OA participants from the Knee Pain and related health in the Community (KPIC) cohort. We next performed gene-based fixed-effects meta-analysis of PPTs and a neuropathic-like pain phenotype using genome-wide association study (GWAS) data from KPIC and from an independent cohort of 613 post-TJR participants, respectively. RESULTS: The most significant genes associated with distal and local sensitization were OR5B3 and BRDT, respectively. We also found previously identified neuropathic pain-associated genes-KCNA1, MTOR, ADORA1 and SCN3B-associated with PPT at the anterior tibia and an inflammatory pain gene-PTAFR-associated with PPT at the lateral joint line. Meta-analysis results of anterior tibia and neuropathic-like pain phenotypes revealed genes associated with bone morphogenesis, neuro-inflammation, obesity, type 2 diabetes, cardiovascular disease and cognitive function. CONCLUSIONS: Overall, our results suggest that different biological processes might be involved in distal and local sensitization, and common genetic mechanisms might be implicated in distal sensitization and neuropathic-like pain. Future studies are needed to replicate these findings. SIGNIFICANCE: To the best of our knowledge, this is the first GWAS for pain sensitization and the first gene-based meta-analysis of pain sensitization and neuropathic-like pain. Higher pain sensitization and neuropathic pain symptoms are associated with persistent pain after surgery hence, identifying genetic biomarkers and molecular pathways associated with these traits is clinically relevant.

Prevalence of steatosis and fibrosis in young adults in the UK: a population-based study.

BACKGROUND: The estimated worldwide prevalence of non-alcoholic fatty liver disease (NAFLD) in adults is 25%; however, prevalence in young adults remains unclear. We aimed to identify the prevalence of steatosis and fibrosis in young adults in a sample of participants recruited through the Avon Longitudinal Study of Parents and Children (ALSPAC), based on transient elastography and controlled attenuation parameter (CAP) score. METHODS: In this population-based study, we invited active participants of the ALSPAC cohort to our Focus@24+ clinic at the University of Bristol (Bristol, UK) between June 5, 2015, and Oct 31, 2017, for assessment by transient elastography with FibroScan, to determine the prevalence of steatosis and fibrosis. FibroScan data were collected on histologically equivalent fibrosis stage (F0-F4) and steatosis grade (S0-S3); results with an IQR to median ratio of 30% or greater were excluded for median fibrosis results greater than 7·1 kPa, and CAP scores for steatosis were excluded if less than ten valid readings could be obtained. Results were collated with data on serology (including alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transferase) and exposures of interest: alcohol consumption (via the Alcohol Use Disorder Identification Test for Consumption [AUDIT-C] and the Diagnostic and Statistical Manual of Mental Disorders-5 criteria for alcohol use disorder), body-mass index (BMI), waist-to-height ratio, socioeconomic status (based on predefined ALSPAC markers), and sex. We used logistic regression models to calculate odds ratios (ORs) for the effect of exposures of interest on risk of steatosis and fibrosis, after dichotomising the prevalences of fibrosis and steatosis and adjusting for covariates (excessive alcohol intake [hazardous drinking, AUDIT-C score ≥5; or harmful drinking, evidence of alcohol use disorder], social class, smoking, and BMI). FINDINGS: 10 018 active ALSPAC participants were invited to our Focus@24+ clinic, and 4021 attended (1507 men and 2514 women), with a mean age of 24·0 years (IQR 23·0-25·0). 3768 CAP scores were eligible for analysis. 780 (20·7% [95% CI 19·4-22·0]) participants had suspected steatosis (S1-S3; ≥248 dB/m), with 377 (10·0%) presenting with S3 (severe) steatosis (≥280 dB/m). A BMI in the overweight or obese range was positively associated with steatosis when adjusted for excessive alcohol consumption, social class, and smoking (overweight BMI: OR 5·17 [95% CI 4·11-6·50], p<0·0001; obese BMI: 27·27 [20·54-36·19], p<0·0001). 3600 participants had valid transient elastography results for fibrosis analysis. 96 participants (2·7% [95% CI 2·2-3·2]) had transient elastography values equivalent to suspected fibrosis (F2-F4; ≥7·9 kPa), nine of whom had values equivalent to F4 fibrosis (≥11·7 kPa). Individuals with alcohol use disorder and steatosis had an increased risk of fibrosis when adjusted for smoking and social class (4·02 [1·24-13·02]; p=0·02). INTERPRETATION: One in five young people had steatosis and one in 40 had fibrosis around the age of 24 years. The risk of fibrosis appears to be greatest in young adults who have harmful drinking patterns and steatosis. A holistic approach to the UK obesity epidemic and excessive drinking patterns is required to prevent an increasing health-care burden of adults with advanced liver disease in later life. FUNDING: Medical Research Council UK, Alcohol Change UK, David Telling Charitable Trust.

Use of prescription analgesic medication and pain catastrophizing after total joint replacement surgery.

OBJECTIVE: To survey the use of analgesic medication 4.8 years after total joint replacement (TJR) surgery and assess the determinants of medication usage. PATIENTS AND METHODS: Of 852 patients who had undergone TJR for osteoarthritis were recruited from secondary care. Participants (mean age, 73.7 years) responded to a questionnaire on medication use, physical function and pain (WOMAC, VAS and body pain), pain catastrophizing and illness behaviour (somatization). RESULTS: Only 37% of study participants were not on any pain relief medication, 25.1% were taking opioids, 6.9% were taking prescription NSAIDs and 25.9% were taking only non-prescription analgesics. Use of NSAIDs correlated with presence of back pain, body pain and high illness behaviour. The strongest associations with use of opioids were severe joint pain, high pain catastrophizing, body and back pain. After adjustment for covariates plus presence of pain, catastrophizing remained significantly associated with higher risk of opioid use (OR = 1.66, 95% CI: 1.13-2.43, p < 0.009) and of other prescription medication that can be used to treat pain (anti-depressants, anti-epileptics and hypnotics) (OR = 2.52, 95% CI: 1.61-3.95, p < 0.0005). CONCLUSIONS: Use of opioid medication 4 years post-TJR is very high in our study population. In addition to joint, back and body pain, a major contributor to opioid use is pain catastrophizing. Our data suggest that current opioid and other analgesic prescribing patterns may benefit from considering the catastrophizing characteristics of patients.