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Objective Whether metformin and its adenosine 5'monophosphate-activated protein kinase (AMPK) activation protect from psoriasis risk is unconcluded. We investigated the effect of AMPK, a pharmacological target of metformin, on the risk of psoriasis and its comorbidities and mortality among participants in the UK Biobank (UKB). Methods To avoid immortal time biases in pharmacoepidemiologic studies, Mendelian randomization was used to infer the AMPK pathway-dependent effects. The cut-off age for distinguishing early-onset/late-onset psoriasis (EOP/LOP) was set at 60 years, based on the incident psoriasis peak in UKB. A genetic instrument comprising 44 single-nucleotide polymorphisms associated with glycated haemoglobin (HbA1c), serving as a proxy for AMPK genetic risk score (negatively associated with AMPK activation), was employed as previously reported in the literature. Log-binomial models were used to estimate the effect size of AMPK regarding relative risk (RR) and 95% CI. Results A total of 407 159 participants were analysed, including 9126 EOP and 3324 LOP. The AMPK genetic risk score was associated with a 12.4% increase in the risk of LOP in men (RR = 1.124, 95% CI: 1.022–1.236). This association was not significant for EOP or women. AMPK genetic risk score exhibited an elevated risk of ischemic heart disease (RR = 1.217, 95% CI 1.062–1.395) in male psoriasis patients. Conclusions AMPK activation may protect against LOPs and associated ischemic heart disease in men. A sex-specific, comorbidity-targeted intervention for psoriasis is needed. [ABSTRACT FROM AUTHOR]

Background: Pruritus is identified as an adverse drug reaction to arsenic trioxide, but the association of arsenic exposure with pruritus has not been investigated. Methods: A cross‐sectional study was conducted in Shimen, China. A Mendelian randomization analysis was conducted to confirm the causal relationship between genetically predicted percentages of monomethylated arsenic (MMA%) and dimethylated arsenic (DMA%) in urine with chronic pruritus in UK Biobank. A case–control study was then conducted to determine the biomarker for pruritus. Arsenite‐treated mice were used to confirm the biomarker, and von Frey test was used to induce scratching bouts. Last, a randomized, double‐blind, placebo‐controlled trial was conducted to test the efficacy of naloxone in arsenic‐exposed patients with pruritus in Shimen. Results: Hair arsenic (μg/g) showed a dose–response relationship with the intensity of itch in 1079 participants, with odds ratios (OR) of 1.11 for moderate‐to‐severe itch (p = 0.012). The Mendelian randomization analysis confirmed the causal relationship, with ORs of 1.043 for MMA% (p = 0.029) and 0.904 for DMA% (p = 0.077) above versus under median. Serum β‐endorphin was identified as a significant biomarker for the intensity of itch (p < 0.001). Consistently, treatment with arsenite upregulated the level of β‐endorphin (p = 0.002) and induced scratching bouts (p < 0.001) in mice. The randomized controlled trial in 126 participants showed that treatment with sublingual naloxone significantly relieved the intensity of itch in arsenic‐exposed participants in 2 weeks (β = −0.98, p = 0.04). Conclusion: Arsenic exposure is associated with pruritus, and β‐endorphin serves as a biomarker of pruritus. Naloxone relieves pruritus in patients with arseniasis. [ABSTRACT FROM AUTHOR]

• Higher C-reactive protein at baseline was associated with a reduced risk of Parkinson's disease. • No assication was identified between interleukin 6 level at baseline and risk of Parkinson's disease. • Significant and negative genetic correlation was identified between C-reactive protein level and risk of PD. • Higher polygenic risk score of C-reactive protein was associated with a lower risk of PD. Multiple evidence has suggested the complex interplay between Parkinson's disease (PD) and systemic inflammation marked by C-reactive protein (CRP) and interleukin 6 (IL-6). Nevertheless, the findings across studies have shown inconsistency, and the direction of the effect remains controversial. Here, we aimed to explore the link between CRP and IL-6 and the risk of PD. Based on data from the UK Biobank, we investigated the association between baseline CRP and IL-6 and the risk of incident PD with Cox proportional hazards regression analysis. We further performed extensive genetic analyses including genetic correlation, polygenic risk score (PRS), and pleiotropic enrichment based on summary statistics from previous genome-wide association studies. A higher level of CRP at baseline was associated with a lower risk of PD (HR = 0.85, 95 % CI: 0.79–0.90, P = 4.23E−07). The results remained consistent in the subgroup analyses stratified by sex, age and body mass index. From the genetic perspective, a significant negative genetic correlation was identified between CRP and PD risk (correlation: −0.14, P = 6.31E−05). Higher PRS of CRP was associated with a lower risk of PD (P = 0.015, beta = −0.04, SE = 0.017). Moreover, we observed significant pleiotropic enrichment for PD conditional on CRP, and identified 13 risk loci for PD, some of which are implicated in immune functionality and have been linked to PD, including CTSB , HNF4A , PPM1G , ACMSD, and NCOR1. In contrast, no significant association was identified between IL-6 and PD. Systemic inflammation at baseline measured by CRP level is associated with decreased future risk of PD. These discoveries contribute to a deeper comprehension of the role of inflammation in the risk of PD, and hold implications for the design of therapeutic interventions in clinical trials. [ABSTRACT FROM AUTHOR]

• Higher prevalence of frailty and accelerated biological age with SMI than those without SMI. • In this cohort study with over 12 years of follow-up in the UK Biobank, biological aging was strongly and positively associated with the incidence risk of CMDs among people with SMI. • Findings highlight the important implications for concerning about the high incidence of CMDs comorbidities and intervention of aging in people with SMI and may reduce premature mortality and improve life expectancy. Cardiometabolic diseases (CMDs) comorbidities among people with severe mental illnesses (SMI) are associated with a high healthcare burden and premature mortality. This study aims to evaluate whether biological aging has an interaction with SMI on incident CMDs, and to examine the association of four biological aging indicators with CMDs incidence in this population. Data were sourced from the UK Biobank, a large prospective cohort study. Four indicators were used to assess biological aging including frailty phenotype, frailty index, KDM-biological age acceleration and phenotypic age acceleration. Cox proportional hazards regression models were used to examine the associations. We observed higher prevalence of frailty and accelerated biological age with SMI than those without SMI. Further analysis found significant interaction effect of pre-frailty and SMI (P Pre-frail*SMI =0.005) as well as biological age acceleration and SMI (P Q3 (>P75)*SMI =0.038). 14.7 % of the participants with SMI developed CMDs during the follow-up. Compared with non-frail participants, those with frailty (frailty phenotype: HR=1.68, 95 % CI: 1.50, 1.88, P < 0.001; frailty index: HR=2.44, 95 % CI: 2.11–2.81, P < 0.001) and biological age acceleration (KDM-biological age acceleration (Q3): HR=1.91, 95 % CI: 1.74, 2.11, P < 0.001; phenotypic age acceleration (Q3): HR=2.07, 95 % CI: 1.86, 2.30, P < 0.001) had a significantly higher risk of CMDs in the adjusted model. A series of sensitivity analyses were conducted to illustrate the robustness of the findings. These findings highlight the important implications for concerning about the high incidence of CMDs comorbidities and intervention of aging in people with SMI. [ABSTRACT FROM AUTHOR]