The overwhelming majority of participants in current genetic studies are of European ancestry. To elucidate disease biology in the East Asian population, we conducted a genome-wide association study ...(GWAS) with 212,453 Japanese individuals across 42 diseases. We detected 320 independent signals in 276 loci for 27 diseases, with 25 novel loci (P < 9.58 × 10
). East Asian-specific missense variants were identified as candidate causal variants for three novel loci, and we successfully replicated two of them by analyzing independent Japanese cohorts; p.R220W of ATG16L2 (associated with coronary artery disease) and p.V326A of POT1 (associated with lung cancer). We further investigated enrichment of heritability within 2,868 annotations of genome-wide transcription factor occupancy, and identified 378 significant enrichments across nine diseases (false discovery rate < 0.05) (for example, NKX3-1 for prostate cancer). This large-scale GWAS in a Japanese population provides insights into the etiology of complex diseases and highlights the importance of performing GWAS in non-European populations.
Clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) represent two forms of clonal hematopoiesis where clones bearing expanded somatic mutations have been ...linked to both oncologic and non-oncologic clinical outcomes including atherosclerosis and all-cause mortality. Epidemiologic studies have highlighted smoking as an important driver of somatic mutations across multiple tissues. However, establishing the causal role of smoking in clonal hematopoiesis has been limited by observational study designs, which may suffer from confounding and reverse-causality. We performed two complementary analyses to investigate the role of smoking in mCAs and CHIP. First, using an observational study design among UK Biobank participants, we confirmed strong associations between smoking and mCAs. Second, using two-sample Mendelian randomization, smoking was strongly associated with mCA but not with CHIP. Overall, these results support a causal association between smoking and mCAs and suggest smoking may variably shape the fitness of clones bearing somatic mutations.
While most patients with myocardial infarction (MI) have underlying coronary atherosclerosis, not all patients with coronary artery disease (CAD) develop MI. We sought to address the hypothesis that ...some of the genetic factors which establish atherosclerosis may be distinct from those that predispose to vulnerable plaques and thrombus formation.
We carried out a genome-wide association study for MI in the UK Biobank (n∼472 000), followed by a meta-analysis with summary statistics from the CARDIoGRAMplusC4D Consortium (n∼167 000). Multiple independent replication analyses and functional approaches were used to prioritize loci and evaluate positional candidate genes. Eight novel regions were identified for MI at the genome wide significance level, of which effect sizes at six loci were more robust for MI than for CAD without the presence of MI. Confirmatory evidence for association of a locus on chromosome 1p21.3 harbouring choline-like transporter 3 (SLC44A3) with MI in the context of CAD, but not with coronary atherosclerosis itself, was obtained in Biobank Japan (n∼165 000) and 16 independent angiography-based cohorts (n∼27 000). Follow-up analyses did not reveal association of the SLC44A3 locus with CAD risk factors, biomarkers of coagulation, other thrombotic diseases, or plasma levels of a broad array of metabolites, including choline, trimethylamine N-oxide, and betaine. However, aortic expression of SLC44A3 was increased in carriers of the MI risk allele at chromosome 1p21.3, increased in ischaemic (vs. non-diseased) coronary arteries, up-regulated in human aortic endothelial cells treated with interleukin-1β (vs. vehicle), and associated with smooth muscle cell migration in vitro.
A large-scale analysis comprising ∼831 000 subjects revealed novel genetic determinants of MI and implicated SLC44A3 in the pathophysiology of vulnerable plaques.
Background
Transoral surgery (TOS) has been used to remove pharyngeal and laryngeal cancers with the objective of improving functional without worsening survival. However, there is a risk of ...postoperative dysphagia, which can severely impair quality of life. The aim of this study was to evaluate the preoperative predictive factors for postoperative dysphagia in patients undergoing TOS.
Methods
One hundred and twenty patients who underwent TOS were evaluated in this study. The degree of dysphagia was evaluated using the Functional Outcome Swallowing Scale (FOSS) both preoperatively and 3 months postoperatively. Those whose FOSS stage was maintained postoperatively were classified into the FOSS-M group, while those with increased FOSS stage postopratively were classified into the FOSS-I group. The following parameters were assessed before surgery: age, weight, height, body mass index (BMI), forced expiratory volume in 1 s, and history of head and neck radiotherapy. Videofluoroscopy (VF) was performed preoperatively to evaluate swallowing function using the Penetration-Aspiration Scale (PAS).
Results
The BMI of the FOSS-M group was significantly higher than that of the FOSS-I group. A history of radiotherapy was significantly more common in the FOSS-I group than in the FOSS-M group. Finally, preoperative PAS in the FOSS-M group was lower than that in the FOSS-I group.
Conclusion
This study suggested that patients with preoperative aspiration detected using VF might develop postoperative dysphagia severely. In addition, preoperative low BMI and a history of previous radiotherapy for head and neck cancer were associated with postoperative dysphagia. Objective examinations such as VF should be performed preoperatively.
We report a genome-wide association study (GWAS) of coronary artery disease (CAD) incorporating nearly a quarter of a million cases, in which existing studies are integrated with data from cohorts of ...white, Black and Hispanic individuals from the Million Veteran Program. We document near equivalent heritability of CAD across multiple ancestral groups, identify 95 novel loci, including nine on the X chromosome, detect eight loci of genome-wide significance in Black and Hispanic individuals, and demonstrate that two common haplotypes at the 9p21 locus are responsible for risk stratification in all populations except those of African origin, in which these haplotypes are virtually absent. Moreover, in the largest GWAS for angiographically derived coronary atherosclerosis performed to date, we find 15 loci of genome-wide significance that robustly overlap with established loci for clinical CAD. Phenome-wide association analyses of novel loci and polygenic risk scores (PRSs) augment signals related to insulin resistance, extend pleiotropic associations of these loci to include smoking and family history, and precisely document the markedly reduced transferability of existing PRSs to Black individuals. Downstream integrative analyses reinforce the critical roles of vascular endothelial, fibroblast, and smooth muscle cells in CAD susceptibility, but also point to a shared biology between atherosclerosis and oncogenesis. This study highlights the value of diverse populations in further characterizing the genetic architecture of CAD.
Drug-induced liver injury (DILI) is a common reason for withdrawal of candidate drugs from clinical trials, or of approved drugs from the market. DILI may be induced not only by intact parental ...drugs, but also by metabolites or intermediates, and therefore should be evaluated in the enzyme-induced state. Here, we present a protocol for assay of drug-metabolizing enzyme-inducing potential using three-dimensional (3D) primary cultures of human hepatocytes (hepatocyte spheroids). Hepatocyte spheroids could be used up to 21 d after seeding (pre-culture for 7 d and exposure to inducer for up to 14 d), based on preliminary evaluation of basal activities of CYP subtypes and mRNA expression of the corresponding transcription factor and xenobiotic receptors (aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR) and pregnane X receptor (PXR)). After 2 d exposure of hepatocyte spheroids to omeprazole, phenobarbital and rifampicin (typical inducers of CYP1A2, 2B6 and 3A4, respectively), CYP1A2, 2B6 and 3A4 mRNA expression levels were significantly increased. The mRNA induction of CYP2B6 remained reasonably stable between days 2 and 14 of exposure to inducers, while induction of both CYP1A2 and 3A4 continued to increase up to day 14. These enzyme activities were all significantly increased compared with the control until day 14. Our findings indicate that our 3D hepatocyte spheroids system would be especially suitable for long-term testing of enzyme activity induction by drugs, either to predict or to verify clinical events.
Heart failure and atherosclerosis share the underlying mechanisms of chronic inflammation followed by fibrosis. A highly conserved microRNA (miR), miR-33, is considered as a potential therapeutic ...target for atherosclerosis because it regulates lipid metabolism and inflammation. However, the role of miR-33 in heart failure remains to be elucidated.
To clarify the role of miR-33 involved in heart failure.
We first investigated the expression levels of miR-33a/b in human cardiac tissue samples with dilated cardiomyopathy. Increased expression of miR-33a was associated with improving hemodynamic parameters. To clarify the role of miR-33 in remodeling hearts, we investigated the responses to pressure overload by transverse aortic constriction in miR-33-deficient (knockout KO) mice. When mice were subjected to transverse aortic constriction, miR-33 expression levels were significantly upregulated in wild-type left ventricles. There was no difference in hypertrophic responses between wild-type and miR-33KO hearts, whereas cardiac fibrosis was ameliorated in miR-33KO hearts compared with wild-type hearts. Despite the ameliorated cardiac fibrosis, miR-33KO mice showed impaired systolic function after transverse aortic constriction. We also found that cardiac fibroblasts were mainly responsible for miR-33 expression in the heart. Deficiency of miR-33 impaired cardiac fibroblast proliferation, which was considered to be caused by altered lipid raft cholesterol content. Moreover, cardiac fibroblast-specific miR-33-deficient mice also showed decreased cardiac fibrosis induced by transverse aortic constriction as systemic miR-33KO mice.
Our results demonstrate that miR-33 is involved in cardiac remodeling, and it preserves lipid raft cholesterol content in fibroblasts and maintains adaptive fibrotic responses in the remodeling heart.
The quick sequential organ failure assessment (qSOFA) score has recently been introduced to the emergency department (ED) and wards, and it predicted a higher number of deaths among patients with ...sepsis compared with baseline risk. However, studies about the application of the qSOFA score are limited in prehospital settings. Thus, this study aimed to assess the performance of prehospital qSOFA score in predicting the risk of mortality among patients with infection.
This single center, retrospective cohort study was conducted in a Japanese tertiary care teaching hospital between April 2016 and March 2017. We enrolled all consecutive adult patients transported to the hospital by ambulance and admitted to the ED due to a suspected infection. We calculated the prehospital qSOFA score using the first vital sign obtained at the scene by emergency medical service (EMS) providers. The primary outcome was in-hospital mortality. The Cox proportional hazards model was used to assess the association between prehospital qSOFA positivity and in-hospital mortality.
Among the 925 patients admitted to the ED due to a suspected infection, 51.1% (473/925) were prehospital qSOFA-positive and 48.9% (452/925) were prehospital qSOFA-negative. The in-hospital mortality rates were 14.0% (66/473) in prehospital qSOFA-positive patients and 6.0% (27/452) in prehospital qSOFA-negative patients. The Cox proportional hazard regression model revealed a strong association between prehospital qSOFA score and in-hospital mortality (adjusted hazard ratio: 2.41, 95% confidence interval: 1.51-3.98; p <0.01).
Among the patients with suspected infection who were admitted at the ED, a strong association was observed between the prehospital qSOFA score and in-hospital mortality. In order to use this score in clinical practice, future study is necessary to evaluate how infection is suspected in the prehospital arena.
Congenital heart diseases often involve maldevelopment of the evolutionarily recent right heart chamber. To gain insight into right heart structure and function, we fine-tuned deep learning models to ...recognize the right atrium, right ventricle and pulmonary artery, measuring right heart structures in 40,000 individuals from the UK Biobank with magnetic resonance imaging. Genome-wide association studies identified 130 distinct loci associated with at least one right heart measurement, of which 72 were not associated with left heart structures. Loci were found near genes previously linked with congenital heart disease, including NKX2-5, TBX5/TBX3, WNT9B and GATA4. A genome-wide polygenic predictor of right ventricular ejection fraction was associated with incident dilated cardiomyopathy (hazard ratio, 1.33 per standard deviation; P = 7.1 × 10
) and remained significant after accounting for a left ventricular polygenic score. Harnessing deep learning to perform large-scale cardiac phenotyping, our results yield insights into the genetic determinants of right heart structure and function.
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