Increased prevalence of advanced liver fibrosis in patients with psoriasis: A cross-sectional analysis from the rotterdam study

Prevalence of non-alcoholic fatty liver disease is increased in patients with psoriasis. However, it is not known how liver fibrosis correlates with psoriasis. This study investigated the association between psoriasis and liver fibrosis compared with participants without psoriasis within the population-based Rotterdam Study. All participants were screened for liver fibrosis using transient elastography. Liver stiffness > 9.5 kPa suggested advanced liver fibrosis. Psoriasis was identified using a validated algorithm. A total of 1,535 participants were included (mean age ± standard deviation 70.5 ± 7.9 years; 50.8% female; median body mass index 26.4 kg/ m2 (interquartile range 24.2–28.9)) of whom 74 (4.7%) had psoriasis. Prevalence of advanced liver fibrosis was 8.1% in psoriasis patients compared with 3.6% in the reference group (p = 0.05). The risk of advanced liver fibrosis in psoriasis patients remained comparable after adjustment for demographics, lifestyle characteristics and laboratory findings (odds ratio 2.57 (95% confidence interval 1.00–6.63). This study suggests that elderly people with psoriasis are twice as likely to have advanced liver fibrosis irrespective of common risk factors

CYP1A2 and coffee intake and the modifying effect of sex, age, and smoking

Background: The enzyme CYP1A2 (cytochrome 1A2) is involved in the metabolism of certain drugs and caffeine, and its activity can be influenced by factors such as sex, age, and smoking. The single nucleotide polymorphism (SNP) rs762551A>C, which has also been studied for its modifying effect on cardiovascular disease, has been reported to alter enzyme activity. Objective: The objective was to study the effect of CYP1A2, sex, age, and smoking on coffee intake. Design: Within the Rotterdam Study, a population-based cohort, all coffee drinkers for whom genome-wide association data were available were selected. Because SNP rs762551 was not on the Illumina 550 platform, SNP rs2472299 was used as a proxy, with the A allele of rs762551 linked to the G allele of rs2472299. Linear regression analyses were used to determine the effect and interaction of rs2472299, sex, age, and smoking on coffee intake. Adjusted geometric means of coffee intake were calculated per genotype for the different smoking and sex strata by using multivariable general linear models. A combined analysis, with the use of a "risk score,"was performed to determine the contribution of each separate factor. Results: rs2472299G>A, female sex, and nonsmoking were significantly inversely related to coffee intake. Coffee intake was lowest in nonsmoking women homozygous for rs2472299G>A (3.49 cups/d; ∼436 mL). All factors contributed almost linearly to the intake of coffee, with the highest coffee intake in smoking men without the A allele (5.32 cups/d; ∼665 mL). Conclusion: rs2472299G>A, linked to rs762551A>C, sex, age, and smoking significantly contribute to coffee intake

Prevalence of pulmonary hypertension in the general population

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A combined linkage and exome sequencing analysis for electrocardiogram parameters in the Erasmus Rucphen family study

Electrocardiogram (ECG) measurements play a key role in the diagnosis and prediction of cardiac arrhythmias and sudden cardiac death. ECG parameters, such as the PR, QRS, and QT intervals, are known to be heritable and genome-wide association studies of these phenotypes have been successful in identifying common variants; however, a large proportion of the genetic variability of these traits remains to be elucidated. The aim of this study was to discover loci potentially harboring rare variants utilizing variance component linkage analysis in 1547 individuals from a large family-based study, the Erasmus Rucphen Family Study (ERF). Linked regions were further explored using exome sequencing. Five suggestive linkage peaks were identified: two for QT interval (1q24, LOD = 2.63; 2q34, LOD = 2.05), one for QRS interval (1p35, LOD = 2.52) and two for PR interval (9p22, LOD = 2.20; 14q11, LOD = 2.29). Fine-mapping using exome sequence data identified a C > G missense variant (c.713C > G, p.Ser238Cys) in the FCRL2 gene associated with QT (rs74608430; P = 2.8 × 10-4, minor allele frequency = 0.019). Heritability analysis demonstrated that the SNP explained 2.42% of the trait's genetic variability in ERF (P = 0.02). Pathway analysis suggested that the gene is involved in cytosolic Ca2+ levels (P = 3.3 × 10-3) and AMPK stimulated fatty acid oxidat

Cross-sectional observational study of 208 patients with non-classical urea cycle disorders.

Urea cycle disorders (UCDs) are inherited disorders of ammonia detoxification often regarded as mainly of relevance to pediatricians. Based on an increasing number of case studies it has become obvious that a significant number of UCD patients are affected by their disease in a non-classical way: presenting outside the newborn period, following a mild course, presenting with unusual clinical features, or asymptomatic patients with only biochemical signs of a UCD. These patients are surviving into adolescence and adulthood, rendering this group of diseases clinically relevant to adult physicians as well as pediatricians. In preparation for an international workshop we collected data on all patients with non-classical UCDs treated by the participants in 20 European metabolic centres. Information was collected on a cohort of 208 patients 50% of which were ≥ 16 years old. The largest subgroup (121 patients) had X-linked ornithine transcarbamylase deficiency (OTCD) of whom 83 were female and 29% of these were asymptomatic. In index patients, there was a mean delay from first symptoms to diagnosis of 1.6 years. Cognitive impairment was present in 36% of all patients including female OTCD patients (in 31%) and those 41 patients identified presymptomatically following positive newborn screening (in 12%). In conclusion, UCD patients with non-classical clinical presentations require the interest and care of adult physicians and have a high risk of neurological complications. To improve the outcome of UCDs, a greater awareness by health professionals of the importance of hyperammonemia and UCDs, and ultimately avoidance of the still long delay to correctly diagnose the patients, is crucial

Overcoming enzalutamide resistance in metastatic prostate cancer by targeting sphingosine kinase

Background Intrinsic resistance to androgen receptor signalling inhibitors (ARSI) occurs in 20–30% of men with metastatic castration-resistant prostate cancer (mCRPC). Ceramide metabolism may have a role in ARSI resistance. Our study's aim is to investigate the association of the ceramide-sphingosine-1-phosphate (ceramide-S1P) signalling axis with ARSI resistance in mCRPC. Methods Lipidomic analysis (∼700 lipids) was performed on plasma collected from 132 men with mCRPC, before commencing enzalutamide or abiraterone. AR gene aberrations in 77 of these men were identified by deep sequencing of circulating tumour DNA. Associations between circulating lipids, radiological progression-free survival (rPFS) and overall survival (OS) were examined by Cox regression. Inhibition of ceramide-S1P signalling with sphingosine kinase (SPHK) inhibitors (PF-543 and ABC294640) on enzalutamide efficacy was investigated with in vitro assays, and transcriptomic and lipidomic analyses of prostate cancer (PC) cell lines (LNCaP, C42B, 22Rv1). Findings Men with elevated circulating ceramide levels had shorter rPFS (HR=2·3, 95% CI=1·5–3·6, p = 0·0004) and shorter OS (HR=2·3, 95% CI=1·4–36, p = 0·0005). The combined presence of an AR aberration with elevated ceramide levels conferred a worse prognosis than the presence of only one or none of these characteristics (median rPFS time = 3·9 vs 8·3 vs 17·7 months; median OS time = 8·9 vs 19·8 vs 34·4 months). SPHK inhibitors enhanced enzalutamide efficacy in PC cell lines. Transcriptomic and lipidomic analyses indicated that enzalutamide combined with SPHK inhibition enhanced PC cell death by SREBP-induced lipotoxicity. Interpretation Ceramide-S1P signalling promotes ARSI resistance, which can be reversed with SPHK inhibitors.Hui-Ming Lin, Blossom Mak, Nicole Yeung, Kevin Huynh, Thomas G. Meikl, Natalie A. Mellett, Edmond M. Kwan, Heidi Fettk, Ben Tran, Ian D. Davis, Kate L. Mahon, Alison Zhang, Martin R. Stockler, Karen Brisco, Gavin Marx, Megan Crumbaker, Phillip D. Stricker, Pan Du, Jianjun Yu, Shidong Ji, Tahlia Scheinberg, Michael Fitzpatrick, Paul Bonnitcha, David R. Sullivan, Anthony M. Joshua, Arun A. Azad, Lisa M. Butler, Peter J. Meikle, Lisa G. Horvat