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Background: Smooth muscle cells (SMC) play a critical role in atherosclerosis. The Aryl hydrocarbon receptor (AHR) is an environment-sensing transcription factor that contributes to vascular development, and has been implicated in coronary artery disease risk. We hypothesized that AHR can affect atherosclerosis by regulating phenotypic modulation of SMC.Methods: We combined RNA-sequencing, chromatin immunoprecipitation followed by sequencing, assay for transposase-accessible chromatin using sequencing, and in vitro assays in human coronary artery SMCs, with single-cell RNA-sequencing, histology, and RNAscope in an SMC-specific lineage-tracing Ahr knockout mouse model of atherosclerosis to better understand the role of AHR in vascular disease.Results: Genomic studies coupled with functional assays in cultured human coronary artery SMCs revealed that AHR modulates the human coronary artery SMC phenotype and suppresses ossification in these cells. Lineage-tracing and activity-tracing studies in the mouse aortic sinus showed that the Ahr pathway is active in modulated SMCs in the atherosclerotic lesion cap. Furthermore, single-cell RNA-sequencing studies of the SMC-specific Ahr knockout mice showed a significant increase in the proportion of modulated SMCs expressing chondrocyte markers such as Col2a1 and Alpl, which localized to the lesion neointima. These cells, which we term "chondromyocytes," were also identified in the neointima of human coronary arteries. In histological analyses, these changes manifested as larger lesion size, increased lineage-traced SMC participation in the lesion, decreased lineage-traced SMCs in the lesion cap, and increased alkaline phosphatase activity in lesions in the Ahr knockout in comparison with wild-type mice. We propose that AHR is likely protective based on these data and inference from human genetic analyses.Conclusions: Overall, we conclude that AHR promotes the maintenance of lesion cap integrity and diminishes the disease-related SMC-to-chondromyocyte transition in atherosclerotic tissues. [ABSTRACT FROM AUTHOR]

Objective: Women with a family history of ovarian cancer or a pathogenic or likely pathogenic gene variant are at high risk of the disease, but very few women have these risk factors. We assessed whether a combined polygenic and clinical risk score could predict risk of ovarian cancer in population-based women who would otherwise be considered as being at average risk., Methods: We used the UK Biobank to conduct a prospective cohort study assessing the performance of 10-year ovarian cancer risks based on a polygenic risk score, a clinical risk score and a combined risk score. We used Cox regression to assess association, Harrell's C-index to assess discrimination and Poisson regression to assess calibration., Results: The combined risk model performed best and problems with calibration were overcome by recalibrating the model, which then had a hazard ratio per quintile of risk of 1.338 [95% confidence interval (CI), 1.152-1.553], a Harrell's C-index of 0.663 (95% CI, 0.629-0.698) and overall calibration of 1.000 (95% CI, 0.874-1.145). In the refined model with estimates based on the entire dataset, women in the top quintile of 10-year risk were at 1.387 (95% CI, 1.086-1.688) times increased risk, while women in the top quintile of full-lifetime risk were at 1.527 (95% CI, 1.187-1.866) times increased risk compared with the population., Conclusion: Identification of women who are at high risk of ovarian cancer can allow healthcare providers and patients to engage in joint decision-making discussions around the risks and benefits of screening options or risk-reducing surgery., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Many studies have shown that IKAROS family zinc finger 1 (IKZF1) rs4132601 polymorphism is strongly linked to acute lymphoblastic leukemia (ALL) in children, but their conclusions have been inconsistent., Objective: This meta-analysis is set out to investigate the association between IKZF1 rs4132601 polymorphism and its susceptibility to childhood ALL., Data and Methods: On the basis of inclusion criteria, PubMed, EMBASE, Web of Science, CNKI, China Wanfang, VIP, and other databases were searched from the time of the establishment of the library database to December 2019 for all case-control studies. Stata 15.0 was applied for meta-analysis to calculate the combined odds ratio (OR) value and 95% confidence interval (CI) of each genotype at IKZF1 rs4132601. Subgroup analysis done by ethnicity, sensitivity analysis, and publication bias assessment was further performed., Results: Nine pieces of literature was included in this meta-analysis, including 2281 children with ALL and 2923 controls. There were significant differences in the allelic model (T vs. G: combined OR=0.75, 95% CI: 0.68-0.82, P<0.05) in both Asian and Caucasian children. In addition to this, there were statistically significant differences in the dominant, homozygous and heterozygous genetic model in both Asian and Caucasian children. The difference was significant in the recessive genetic model (TT vs. TG+GG: combined OR=0.75, 95% CI: 0.67-0.84) in Caucasian children, but not in Asian children (combined OR=0.85, 95% CI: 0.70-1.04, P>0.05)., Conclusion: There is a strong correlation between IKZF1 rs4132601 polymorphism and ALL in children. Compared with the G allele, T alleles can lower the risk of childhood ALL, and TT, TT+TG and TG genotypes can also reduce the risk of ALL in children., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The most prominent risk factor for atrial fibrillation (AF) is chronological age; however, underlying mechanisms are unexplained. Algorithms using epigenetic modifications to the human genome effectively predict chronological age. Chronological and epigenetic predicted ages may diverge in a phenomenon referred to as epigenetic age acceleration (EAA), which may reflect accelerated biological aging. We sought to evaluate for associations between epigenetic age measures and incident AF., Methods: Measures for 4 epigenetic clocks (Horvath, Hannum, DNA methylation [DNAm] PhenoAge, and DNAm GrimAge) and an epigenetic predictor of PAI-1 (plasminogen activator inhibitor-1) levels (ie, DNAm PAI-1) were determined for study participants from 3 population-based cohort studies. Cox models evaluated for associations with incident AF and results were combined via random-effects meta-analyses. Two-sample summary-level Mendelian randomization analyses evaluated for associations between genetic instruments of the EAA measures and AF., Results: Among 5600 participants (mean age, 65.5 years; female, 60.1%; Black, 50.7%), there were 905 incident AF cases during a mean follow-up of 12.9 years. Unadjusted analyses revealed all 4 epigenetic clocks and the DNAm PAI-1 predictor were associated with statistically significant higher hazards of incident AF, though the magnitudes of their point estimates were smaller relative to the associations observed for chronological age. The pooled EAA estimates for each epigenetic measure, with the exception of Horvath EAA, were associated with incident AF in models adjusted for chronological age, race, sex, and smoking variables. After multivariable adjustment for additional known AF risk factors that could also potentially function as mediators, pooled EAA measures for 2 clocks remained statistically significant. Five-year increases in EAA measures for DNAm GrimAge and DNAm PhenoAge were associated with 19% (adjusted hazard ratio [HR], 1.19 [95% CI, 1.09-1.31]; P <0.01) and 15% (adjusted HR, 1.15 [95% CI, 1.05-1.25]; P <0.01) higher hazards of incident AF, respectively. Mendelian randomization analyses for the 5 EAA measures did not reveal statistically significant associations with AF., Conclusions: Our study identified adjusted associations between EAA measures and incident AF, suggesting that biological aging plays an important role independent of chronological age, though a potential underlying causal relationship remains unclear. These aging processes may be modifiable and not constrained by the immutable factor of time.

Background: Atrial fibrillation (AF) risk estimation using clinical factors with or without genetic information may identify AF screening candidates more accurately than the guideline-based age threshold of ≥65 years., Methods: We analyzed 4 samples across the United States and Europe (derivation: UK Biobank; validation: FINRISK, Geisinger MyCode Initiative, and Framingham Heart Study). We estimated AF risk using the CHARGE-AF (Cohorts for Heart and Aging Research in Genomic Epidemiology AF) score and a combination of CHARGE-AF and a 1168-variant polygenic score (Predict-AF). We compared the utility of age, CHARGE-AF, and Predict-AF for predicting 5-year AF by quantifying discrimination and calibration., Results: Among 543 093 individuals, 8940 developed AF within 5 years. In the validation sets, CHARGE-AF (C index range, 0.720-0.824) and Predict-AF (0.749-0.831) had largely comparable discrimination, both favorable to continuous age (0.675-0.801). Calibration was similar using CHARGE-AF (slope range, 0.67-0.87) and Predict-AF (0.65-0.83). Net reclassification improvement using Predict-AF versus CHARGE-AF was modest (net reclassification improvement range, 0.024-0.057) but more favorable among individuals aged <65 years (0.062-0.11). Using Predict-AF among 99 530 individuals aged ≥65 years across each sample, 70 849 had AF risk <5%, of whom 69 067 (97.5%) did not develop AF, whereas 28 681 had AF risk ≥5%, of whom 2264 (7.9%) developed AF. Of 11 379 individuals aged <65 years with AF risk ≥5%, 435 (3.8%) developed AF before age 65 years, with roughly half (46.9%) meeting anticoagulation criteria., Conclusions: AF risk estimation using clinical factors may prioritize individuals for AF screening more precisely than the age threshold endorsed in current guidelines. The additional value of genetic predisposition is modest but greatest among younger individuals.

Background: Genetic testing can determine family screening strategies and has prognostic and diagnostic value in hypertrophic cardiomyopathy (HCM). However, it can also pose a significant psychosocial burden. Conventional scoring systems offer modest ability to predict genotype positivity. The aim of our study was to develop a novel prediction model for genotype positivity in patients with HCM by applying machine learning (ML) algorithms., Methods: We constructed 3 ML models using readily available clinical and cardiac imaging data of 102 patients from Columbia University with HCM who had undergone genetic testing (the training set). We validated model performance on 76 patients with HCM from Massachusetts General Hospital (the test set). Within the test set, we compared the area under the receiver operating characteristic curves (AUROCs) for the ML models against the AUROCs generated by the Toronto HCM Genotype Score (the Toronto score) and Mayo HCM Genotype Predictor (the Mayo score) using the Delong test and net reclassification improvement., Results: Overall, 63 of the 178 patients (35%) were genotype positive. The random forest ML model developed in the training set demonstrated an AUROC of 0.92 (95% CI, 0.85-0.99) in predicting genotype positivity in the test set, significantly outperforming the Toronto score (AUROC, 0.77 [95% CI, 0.65-0.90], P =0.004, net reclassification improvement: P <0.001) and the Mayo score (AUROC, 0.79 [95% CI, 0.67-0.92], P =0.01, net reclassification improvement: P =0.001). The gradient boosted decision tree ML model also achieved significant net reclassification improvement over the Toronto score ( P <0.001) and the Mayo score ( P =0.03), with an AUROC of 0.87 (95% CI, 0.75-0.99). Compared with the Toronto and Mayo scores, all 3 ML models had higher sensitivity, positive predictive value, and negative predictive value., Conclusions: Our ML models demonstrated a superior ability to predict genotype positivity in patients with HCM compared with conventional scoring systems in an external validation test set.

Abstract: Some patients with advanced colon adenocarcinoma (COAD) are not sensitive to radiotherapy and chemotherapy, and as such, immunotherapy has become the most popular option for these patients. However, different patients respond differently to immunotherapy. Tumor mutational burden (TMB) has been used as a predictor of the response of advanced COAD patients to immunotherapy. A high TMB typically indicates that the patient's immune system will respond well to immunotherapy. In addition, while microRNAs (miRNA) have been shown to play an important role in treatment responses associated with the immune system, the relationship between miRNA expression levels and TMB has not been clarified in COAD.We downloaded miRNA data and mutational files of COAD from the Cancer Genome Atlas database. Differentially expressed miRNAs were screened in the training group, and miRNAs used to construct the model were further identified using the LASSO logistic regression method. After building the miRNA-based model, we explored the correlation between the model and TMB. The model was verified by a receiver operating characteristic curve, and the correlation between it and 3 widely used immune checkpoints (programmed death receptor-1, programmed death-ligand 1, and cytotoxic T-lymphocyte associated protein-4) was explored. Functional enrichment analysis of the selected miRNAs was performed, and these respective miRNA target genes were predicted using online tools.Our results showed that a total of 32 differentially expressed miRNAs were used in the construction of the model. The accuracies of the models of the 2 datasets (training and test sets) were 0.987 and 0.934, respectively. Correlation analysis showed that the correlation of the model with programmed death-ligand 1 and cytotoxic T-lymphocyte associated protein-4, as well as TMB, was high, but there was no correlation with programmed death receptor-1. The results of functional enrichment analysis indicated that these 32 miRNAs were involved in many immune-related biological processes and tumor-related pathways.Therefore, this study demonstrated that differentially expressed miRNAs can be used to predict the TMB level, which can help identify advanced COAD patients who will respond well to immunotherapy. The miRNA-based model may be used as a tool to predict the TMB level in patients with advanced COAD., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

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Abstract: Study has demonstrated that TNIP1 polymorphisms are associated with an increased risk of HBV-induced hepatocellular carcinoma (HCC). The purpose of this study was to investigate the correlation between polymorphisms in TNIP1 and HCC risk in a Northwest Chinese Han population.A case-control study was conducted including 473 Hepatocellular carcinoma patients and 564 healthy controls. Three SNPs (rs3792792, rs7708392, and rs10036748) were genotyped with Sequenom MassARRAY technology and their associations with HCC risk were analyzed. These data were evaluated using the Chi-square test/Fisher's exact test, genetic model analysis, and haplotype analysis. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the association.Patients with the "G" allele of TNIP1 rs7708392 showed a significantly increased risk of HCC (OR = 1.24, 95%CI: 1.01-1.52, P = .042). Significant association was also shown between TNIP1 rs7708392 and HCC susceptibility in Additive model (OR = 1.25; 95% CI = 1.01-1.54; P = .040). Besides, we also found that the "GC" haplotype of rs7708392 and rs10036748 was significantly associated with higher occurrence of HCC (OR = 1.25, 95% CI: 1.01-1.54, P = .039).These results demonstrate that TNIP1 polymorphisms are associated with increased HCC risk in a Northwest Chinese Han population for the first time, which warrants further investigation in the future., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: Greater leisure-time physical activity (LTPA) associates with healthier lives, but knowledge regarding occupational physical activity (OPA) is more inconsistent. DNA methylation (DNAm) patterns capture age-related changes in different tissues. We aimed to assess how LTPA and OPA are associated with three DNAm-based epigenetic age estimates, namely, DNAm age, PhenoAge, and GrimAge., Methods: The participants were young adult (21-25 yr, n = 285) and older (55-74 yr, n = 235) twin pairs, including 16 pairs with documented long-term LTPA discordance. Genome-wide DNAm from blood samples was used to compute DNAm age, PhenoAge, and GrimAge Age acceleration (Acc), which describes the difference between chronological and epigenetic ages. Physical activity was assessed with sport, leisure-time, and work indices based on the Baecke Questionnaire. Genetic and environmental variance components of epigenetic age Acc were estimated by quantitative genetic modeling., Results: Epigenetic age Acc was highly heritable in young adult and older twin pairs (~60%). Sport index was associated with slower and OPA with faster DNAm GrimAge Acc after adjusting the model for sex. Genetic factors and nonshared environmental factors in common with sport index explained 1.5%-2.7% and 1.9%-3.5%, respectively, of the variation in GrimAge Acc. The corresponding proportions considering OPA were 0.4%-1.8% and 0.7%-1.8%, respectively. However, these proportions were minor (<0.5%) after adjusting the model for smoking status., Conclusions: LTPA associates with slower and OPA with faster epigenetic aging. However, adjusting the models for smoking status, which may reflect the accumulation of unhealthy lifestyle habits, attenuated the associations., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American College of Sports Medicine.)

Background: Atrial fibrillation (AF) often arises from structural abnormalities in the left atria (LA). Annotation of the noncoding genome in human LA is limited, as are effects on gene expression and chromatin architecture. Many AF-associated genetic variants reside in noncoding regions; this knowledge gap impairs efforts to understand the molecular mechanisms of AF and cardiac conduction phenotypes., Methods: We generated a model of the LA noncoding genome by profiling 7 histone post-translational modifications (active: H3K4me3, H3K4me2, H3K4me1, H3K27ac, H3K36me3; repressive: H3K27me3, H3K9me3), CTCF binding, and gene expression in samples from 5 individuals without structural heart disease or AF. We used MACS2 to identify peak regions ( P <0.01), applied a Markov model to classify regulatory elements, and annotated this model with matched gene expression data. We intersected chromatin states with expression quantitative trait locus, DNA methylation, and HiC chromatin interaction data from LA and left ventricle. Finally, we integrated genome-wide association data for AF and electrocardiographic traits to link disease-related variants to genes., Results: Our model identified 21 epigenetic states, encompassing regulatory motifs, such as promoters, enhancers, and repressed regions. Genes were regulated by proximal chromatin states; repressive states were associated with a significant reduction in gene expression ( P <2×10 -16 ). Chromatin states were differentially methylated, promoters were less methylated than repressed regions ( P <2×10 -16 ). We identified over 15 000 LA-specific enhancers, defined by homeobox family motifs, and annotated several cardiovascular disease susceptibility loci. Intersecting AF and PR genome-wide association studies loci with long-range chromatin conformation data identified a gene interaction network dominated by NKX2-5 , TBX3 , ZFHX3 , and SYNPO2L ., Conclusions: Profiling the noncoding genome provides new insights into the gene expression and chromatin regulation in human LA tissue. These findings enabled identification of a gene network underlying AF; our experimental and analytic approach can be extended to identify molecular mechanisms for other cardiac diseases and traits.

Background: Individual risk prediction based on genome-wide polygenic risk scores (PRSs) using millions of genetic variants has attracted much attention. It is under debate whether PRS models can be applied-without loss of precision-to populations of similar ethnic but different geographic background than the one the scores were trained on. Here, we examine how PRS trained in population-specific but European data sets perform in other European subpopulations in distinguishing between coronary artery disease patients and healthy individuals., Methods: We use data from UK and Estonian biobanks (UKB, EB) as well as case-control data from the German population (DE) to develop and evaluate PRS in the same and different populations., Results: PRSs have the highest performance in their corresponding population testing data sets, whereas their performance significantly drops if applied to testing data sets from different European populations. Models trained on DE data revealed area under the curves in independent testing sets in DE: 0.6752, EB: 0.6156, and UKB: 0.5989; trained on EB and tested on EB: 0.6565, DE: 0.5407, and UKB: 0.6043; trained on UKB and tested on UKB: 0.6133, DE: 0.5143, and EB: 0.6049., Conclusions: This result has a direct impact on the clinical usability of PRS for risk prediction models using PRS: a population effect must be kept in mind when applying risk estimation models, which are based on additional genetic information even for individuals from different European populations of the same ethnicity.

Introduction Schizophrenia is recognized as one of the most important mental illnesses of the last century. Many genetic and environmental factors are involved in this condition. Recently, the genome-wide association study identified two significant genes LRP8 and CEP85L associated with psychiatric disorders. LRP8 (low-density lipoprotein receptor-related protein 8) acts as a cytoplasmic receptor for Reelin. Many studies have revealed that LRP8 was significantly related to schizophrenia and bipolar disorder in Chinese population. CEP85L standing for 'centrosomal protein 85 kDa-like' is another gene, which has been reportedly associated with BPD. Methods We performed a case-control study to analyze the association between rs5177 single-nucleotide polymorphism in the LRP8 gene plus the single-nucleotide polymorphism rs11756438 in the CEP85L gene and schizophrenia in the Iranian population. The genotype for rs5177 was determined by ARMS PCR method, while for rs11756438 genotype, it was determined by PCR-RFLP method after which statistical analysis was performed for each polymorphism. In rs5177, the CC genotype was susceptible to the disease while G allele was associated with disease protection. Results and Conclusion In rs11756438, the AA genotype was associated with disease susceptibility, while allele A did not have a significant association with the disease.

Background: Spontaneous coronary artery dissection (SCAD) occurs when an epicardial coronary artery is narrowed or occluded by an intramural hematoma. SCAD mainly affects women and is associated with pregnancy and systemic arteriopathies, particularly fibromuscular dysplasia. Variants in several genes, such as those causing connective tissue disorders, have been implicated; however, the genetic architecture is poorly understood. Here, we aim to better understand the diagnostic yield of rare variant genetic testing among a cohort of SCAD survivors and to identify genes or gene sets that have a significant enrichment of rare variants., Methods: We sequenced a cohort of 384 SCAD survivors from the United Kingdom, alongside 13 722 UK Biobank controls and a validation cohort of 92 SCAD survivors. We performed a research diagnostic screen for pathogenic variants and exome-wide and gene-set rare variant collapsing analyses., Results: The majority of patients within both cohorts are female, 29% of the study cohort and 14% validation cohort have a remote arteriopathy. Four cases across the 2 cohorts had a diagnosed connective tissue disorder. We identified pathogenic or likely pathogenic variants in 7 genes ( PKD1 , COL3A1 , SMAD3 , TGFB2 , LOX , MYLK , and YY1AP1 ) in 14/384 cases in the study cohort and in 1/92 cases in the validation cohort. In our rare variant collapsing analysis, PKD1 was the highest-ranked gene, and several functionally plausible genes were enriched for rare variants, although no gene achieved study-wide statistical significance. Gene-set enrichment analysis suggested a role for additional genes involved in renal function., Conclusions: By studying the largest sequenced cohort of SCAD survivors, we demonstrate that, based on current knowledge, only a small proportion have a pathogenic variant that could explain their disease. Our findings strengthen the overlap between SCAD and renal and connective tissue disorders, and we highlight several new genes for future validation.

Background: It has been reported that polymorphisms of transferrin (TF) G258A and transferrin receptor (TFR) A82G might be associated with susceptibility to Parkinson disease (PD)., Objective: Owing to limitation of sample size and inconclusive results, we conducted a meta-analysis to clarify the association., Methods: By searching PubMed, Embase, Chinese National Knowledge Infrastructure, China Biological Medicine Database, and Wanfang Databases, the published articles about studies of the association of the TF G258A, TFR A82G gene polymorphisms with the risk of PD were collected. Q-statistics and I statistics were calculated to examine heterogeneity and summary odds ratios (ORs) and 95% confidence intervals (95%CI) were evaluated the association., Results: Five studies assessed the relationship between TF G258A and risk of PD. A significant increased protective of A allele and AA genotype was observed in allele model and recessive model (the allele model A vs G: OR = 0.54, 95%CI 0.40-0.72, P < .001; the recessive model AA vs GA + GG: OR = 0.32, 95%CI 0.20-0.52, P < .001). The remaining models of the TF G258A genotype showed no significant association with PD risk, while the protective tendency were increased (the heterozygote model GA vs GG: OR = 0.93, 95%CI 0.61-1.43, P = .75; the homozygous model AA vs GG: OR = 0.47, 95%CI 0.21-1.04, P = .06; the dominant model GA + AA vs GG: OR = 0.75, 95%CI 0.50-1.11, P = .15). There was also a lack of association between TFR A82G polymorphism and PD (the allele model G vs A: OR = 0.92, 95%CI 0.75-1.13, P = .43; the heterozygote model AG vs AA: OR = 1.17, 95%CI 0.79-1.71, P = .43; the homozygous model GG vs AA: OR = 0.91, 95%CI 0.60-139, P = .66; the dominant model AG + GG vs AA: OR = 1.05, 95%CI 0.73-1.49, P = .81; the recessive model GG vs AG +AA: OR = 0.80, 95%CI 0.59-1.09, P = .16)., Conclusion: Our study suggests that TF G258A polymorphism may be associated with PD, while TFR A82G polymorphism may not contribute to PD based on the current evidence.

Previous studies have evaluated the association between the phospholipase A2 m-type receptor (PLA2R1) rs4664308 polymorphism and the risk of idiopathic membranous nephropathy (IMN), but the results need to be integrated. We hypothesized that the PLA2R1 rs4664308 polymorphism is associated with IMN risk in different ethnicities and assessed this hypothesis by using meta-analysis and case-control studies.A literature searches on PLA2R1 rs4664308 and IMN risk was conducted using the EMBASE, PubMed, Cochrane Library, and Chinese Medical Databases. The relationship between PLA2R1 rs4664308 and IMN risk was evaluated in 5 genetic models, namely, allelic (AG), recessive (RG), dominant (DG), homozygous (HMG), and heterozygous (HTG) models. Subgroup analysis was conducted by ethnicity on Asian and non-Asian populations.Eight sets of data from 6 articles met study objectives were selected and 6797 subjects (IMN: 2324 Controls: 4,473) were included. Heterogeneity was found in the DG, HMG, and HTG models but not in the AG or RG models. The minor allele(G) of PLA2R1 rs4664308 showed a significant negative correlation with IMN risk in all genetic random models: odds ratio of AG: 0.44(0.37-0.51), RG: 0.35(0.29-0.42), DG: 0.38(0.31-0.48), HMG: 0.26(0.19-0.37), and HTG: 0.61(0.48-0.77; P < .00001), and Asians and non-Asians showed the same effect of PLA2R1 rs4664308 on IMN risk. Analysis of Asians and non-Asians revealed no publication bias in any of the 5 genetic models.The minor allele of PLA2R1 rs4664308 has a protective activity against IMN in Asians and non-Asians. It provided new insights into potential curative and preventative treatments for IMN.

Background: In cardiac gene therapy to improve contractile function, achieving gene expression in the majority of cardiac myocytes is essential. In preventing cardiac arrhythmias, however, this goal may not be as important since transduction efficiencies as low as 40% suppressed ventricular arrhythmias in genetically modified mice with catecholaminergic polymorphic ventricular tachycardia., Methods: Using computational modeling, we simulated 1-, 2-, and 3-dimensional tissue under a variety of conditions to test the ability of genetically engineered nonarrhythmogenic stabilizer cells to suppress triggered activity due to delayed or early afterdepolarizations., Results: Due to source-sink relationships in cardiac tissue, a minority (20%-50%) of randomly distributed stabilizer cells engineered to be nonarrhythmogenic can suppress the ability of arrhythmogenic cells to generate delayed and early afterdepolarizations-related arrhythmias. Stabilizer cell gene therapy strategy can be designed to correct a specific arrhythmogenic mutation, as in the catecholaminergic polymorphic ventricular tachycardia mice studies, or more generally to suppress delayed or early afterdepolarizations from any cause by overexpressing the inward rectifier K channel Kir2.1 in stabilizer cells., Conclusions: This promising antiarrhythmic strategy warrants further testing in experimental models to evaluate its clinical potential.

Background and Purpose- A growing body of evidence indicates genetic components play critical roles in moyamoya disease (MMD). Firm conclusions from studies of this disease have been stymied by small sample sizes and a lack of replicative results. This meta-analysis was conducted to determine whether these genetic polymorphisms are associated with MMD. Methods- PubMed, Google Scholar, Embase, Wanfang, Web of Science, and China National Knowledge Infrastructure databases were used to identify potentially relevant studies published until January 2020. The Review Manager 5.2 and Stata 15.0 software programs were used to perform the statistical analysis. Heterogeneity was assessed using the Cochran Q test and quantified using the I 2 test. Results- Four thousand seven hundred eleven MMD cases and 8704 controls in 24 studies were included, evaluating 7 polymorphisms in 6 genes. The fixed-effect odds ratios (95% CI) in allelic model of MMP-2 rs243865 were 0.60 (0.41-0.88) ( P =0.008). In the country-based subgroup analysis, the fixed-effect odds ratios (95% CI) of RNF213 rs112735431 in allelic model were China, 39.74 (26.63-59.31), Japan, 74.65 (42.79-130.24) and Korea, 50.04 (28.83-86.88; all P <0.00001). In the sensitivity analysis, the fixed-effect odds ratios (95% CI) of allelic and dominant models were the RNF213 rs148731719 variant, 2.17 (1.36-3.48; P =0.001), 2.20 (1.35-3.61; P =0.002), the TIMP-2 rs8179090 variant, 0.33 (0.25-0.43; P <0.00001), 0.88 (0.65-1.21; P =0.440) and the MMP-3 rs3025058 variant, 0.61 (0.47-0.79; P =0.0002), 0.55 (0.41-0.75; P =0.0001), respectively. Conclusions- RNF213 rs112735431 and rs148731719 were positively, and TIMP-2 rs8179090, MMP-2 rs243865, and MMP-3 rs3025058 were inversely associated with MMD using multiple pathophysiologic pathways. Studies in larger population should be conducted to clarify whether and how these variants are associated with MMD.

An individual's susceptibility to atherosclerotic cardiovascular disease is influenced by numerous clinical and lifestyle factors, motivating the multifaceted approaches currently endorsed for primary and secondary cardiovascular disease prevention. With growing knowledge of the genetic basis of atherosclerotic cardiovascular disease-in particular, coronary artery disease-and its contribution to disease pathogenesis, there is increased interest in understanding the potential clinical utility of a genetic predictor that might further refine the assessment and management of atherosclerotic cardiovascular disease risk. Rapid scientific and technological advances have enabled widespread genotyping efforts and dynamic research in the field of coronary artery disease genetic risk prediction. In this review, we describe how genomic analyses of coronary artery disease have been leveraged to create polygenic risk scores. We then discuss evaluations of the clinical utility of these scores, pertinent mechanistic insights gleaned, and practical considerations relevant to the implementation of polygenic risk scores in the health care setting.

Our aim was to investigate whether polymorphisms in the interleukin-4 (IL-4) gene are associated with the risk of colorectal cancer (CRC) in a Chinese Han population. Six single-nucleotide polymorphisms (SNPs) in the IL-4 were genotyped by Agena MassARRAY in 248 CRC patients and 463 healthy controls. The association of IL-4 polymorphisms with CRC risk was assessed by genetic models, linkage disequilibrium, and haplotype analyses. The results suggested that the CC genotype of rs2243250 confers a lower risk of CRC in the recessive model [odds ratio (OR) =  0.42, 95% confidence interval (CI): 0.19-0.92, P = 0.020]. Similarly, rs2227284 GG was associated with a reduced risk of CRC in the codominant (OR = 0.18, 95% CI: 0.04-0.82, P = 0.027) and recessive (OR = 0.19, 95% CI: 0.04-0.83, P = 0.008) models adjusted for age. Our findings suggested that rs2243250 and rs2227284 in IL-4 are associated significantly with reduced CRC risk, which may facilitate the identification of CRC patients in Chinese populations.

From the bedside of patients contributing samples to large genome-wide association studies for atrial fibrillation (AF), over 100 AF risk loci have been identified. The top locus is near a gene implicated in pulmonary vein formation; the ostia of the pulmonary veins harbor initiating triggers of AF, and isolation of these areas is the cornerstone of ablation therapies for AF. Transcriptomic studies suggest that AF is associated with impaired or overwhelmed responses to cell stress. A dual risk model proposes that in genetically-susceptible individuals, inadequate transcriptional responses to stress predispose to AF in later life. Drugs targeting metabolic, oxidative, or protein handling stress may be novel upstream agents to bring back to the bedside for study in the prevention of AF.

Objective: Non-syndromic cleft of the lip and/or palate (NSCL/P) is one of the most common polygenic diseases. In this study, both case-control and family-based association study were used to confirm whether the Single Nucleotide Polymorphisms (SNPs) were associated with NSCL/P., Methods: A total of 37 nuclear families and 189 controls were recruited, whose blood DNA was extracted and subjected to genotyping of SNPs of 27 candidate genes by polymerase chain reaction-improved multiple ligase detection reaction technology (PCR-iMLDR). Case-control statistical analysis was performed using the SPSS 19.0. Haplotype Relative Risk (HRR), transmission disequilibrium test (TDT), and Family-Based Association Test (FBAT) were used to test for over-transmission of the target alleles in case-parent trios. The gene-gene interactions on NSCL/P were analyzed by Unphased-3.1.4., Results: In case-control statistical analysis, only C14orf49 chr14&#95;95932477 had statistically significant on genotype model (P = .03) and allele model (P = .03). Seven SNPs had statistically significant on TDT. None of 26 alleles has association with NSCL/P on FBAT. Some SNPs had haplotype-haplotype interactions and genotype-genotype interactions., Conclusion: C14orf49 chr14&#95;95932477 was significantly different between cases and controls on genotype model and allele model by case-control design. Seven SNPs were significantly different on HRR. Four SNPs were significantly different on TDT.

Gelatinous drop-like corneal dystrophy (GDLD; OMIM: 204870) is an autosomal recessive Mendelian-inherited disease. Subepithelial amyloid deposition results in severe visual impairment. Its pathogenesis remains unknown. Identification of the responsible gene is a useful approach to investigating the pathogenesis of genetic diseases. Such an identification is also necessary for the creation of genetic models. For this purpose, our group performed positional cloning using homozygosity mapping. The results revealed that GDLD maps to the short arm of chromosome 1. Subsequent mutation analyses identified tumor-associated calcium signal transducer 2 (TACSTD2; former name, M1S1) as the gene responsible for GDLD. After identification of the gene, we examined the phylogenetical distribution of TACSTD2 in the genomes of vertebrates.

Background: Forkhead box P3 (Foxp3) plays important roles in the development and pathogensis of cancer. To investigate the association of 3 polymorphisms of Foxp3 (rs3761548, rs 3761549 and rs2280883) and cancer risk, an updated meta-analysis was performed., Methods: Around 11 studies including 4344 cancer patients and 4665 healthy controls were selected for this meta-analysis. There were nine studies with 3783 cases and 4096 controls for rs3761548, 4 studies with 1669 cases and 1613 controls for rs3761549 and 4 studies with 1821 cases and 1799 controls for rs2280883. Odds radios (ORs) and 95% confidence intervals (CIs) were used to evaluate the cancer risk., Results: Meta-analysis showed that rs3761548 was associated with an increased cancer risk in the overall population under the recessive model (AA vs CA + CC: OR = 1.45, 95%CI = 1.03-2.02, P = .03). No association was found between rs3761549, rs2280883 polymorphisms, and cancer susceptibility in the overall population. Nonetheless, in the genotyping methods subgroup analysis of rs2280883, a lower risk of cancer was found in studies using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) under the allelic model (C vs T: OR = 0.70, 95%CI = 0.52-0.95, P = .02), heterozygote model (TC vs TT: OR = 0.60, 95%CI = 0.41-0.87, P = .008) and dominant model (CC + TC vs TT: OR = 0.63, 95%CI = 0.45-0.90, P = .01). In the subgroup analysis by cancer types showed C allele or TC carriers were insusceptible to cancer under 3 genetic models (C vs T: OR = 0.78, 95%CI = 0.64-0.95, P = .01; TC vs TT: OR = 0.50, 95%CI = 0.32-0.79, P = .003; CC + TC vs TT: OR = 0.64, 95%CI = 0.51-0.82, P < .001)., Conclusion: Our results suggest that rs3761548 polymorphism is associated with cancer risk.

Background: Accurately predicting the impact of rare nonsynonymous variants on disease risk is an important goal in precision medicine. Variants in the cardiac sodium channel SCN5A (protein Na V 1.5; voltage-dependent cardiac Na+ channel) are associated with multiple arrhythmia disorders, including Brugada syndrome and long QT syndrome. Rare SCN5A variants also occur in ≈1% of unaffected individuals. We hypothesized that in vitro electrophysiological functional parameters explain a statistically significant portion of the variability in disease penetrance., Methods: From a comprehensive literature review, we quantified the number of carriers presenting with and without disease for 1712 reported SCN5A variants. For 356 variants, data were also available for 5 Na V 1.5 electrophysiological parameters: peak current, late/persistent current, steady-state V1/2 of activation and inactivation, and recovery from inactivation., Results: We found that peak and late current significantly associate with Brugada syndrome ( P <0.001; ρ=-0.44; Spearman rank test) and long QT syndrome disease penetrance ( P <0.001; ρ=0.37). Steady-state V1/2 activation and recovery from inactivation associate significantly with Brugada syndrome and long QT syndrome penetrance, respectively. Continuous estimates of disease penetrance align with the current American College of Medical Genetics classification paradigm., Conclusions: Na V 1.5 in vitro electrophysiological parameters are correlated with Brugada syndrome and long QT syndrome disease risk. Our data emphasize the value of in vitro electrophysiological characterization and incorporating counts of affected and unaffected carriers to aid variant classification. This quantitative analysis of the electrophysiological literature should aid the interpretation of Na V 1.5 variant electrophysiological abnormalities and help improve Na V 1.5 variant classification., (© 2018 American Heart Association, Inc.)

Genome-wide association studies and meta-analyses indicate that the polymorphism of rs266729 in adiponectin gene increases the risk of type 2 diabetes mellitus (T2DM); however, these study methods have not been able to identify the underlying genetic effect on the development of T2DM. A genetic model-free approach was conducted to determine the underlying genetic model of inheritance of T2DM because of rs266729 in adiponectin gene.We searched available studies on the association between the rs266729 in adiponectin gene and T2DM in accordance with the inclusion and exclusion criteria. Based on the information extracted from the studies, generalized odds ratio value (GOR) was used to evaluate whether the rs266729 polymorphism was a risk factor for T2DM. The parameter λ was calculated to estimate the genetic model, which was defined as the quotient of natural logarithm odds ratio of GC to CC divided by the natural logarithm odds ratio of GG to CC. Finally, binary logistic regression analysis was used to calculate the genetic effect of rs266729 on T2DM.Data from 7 studies were included in this meta-analysis. The total number of subjects was 12,323, comprising 5,948 cases and 6,395 controls. Mean (standard deviation) age of cases was 59.50 (11.53), and that of the controls was 53.80 (11.65), whereas the proportion of male was 40.9 and 50.0%, respectively. GOR was 1.13 (1.02, 1.25) and λ was 0.47 (0.29, 0.64). The result of logistic regression indicated that the G allele influenced the development of T2DM in the additive model, whereas the genetic effect was 1.13 (1.06, 1.19). Sources of control populations were the cause of between-study heterogeneity; nonetheless, there was no publication bias among studies.The G allele of rs266729 in adiponectin gene increases the risk of T2DM through an additive genetic model with an effect of 1.13 (1.06, 1.19)., (Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background: Studies of recurrent or subsequent disease events may be susceptible to bias caused by selection of subjects who both experience and survive the primary indexing event. Currently, the magnitude of any selection bias, particularly for subsequent time-to-event analysis in genetic association studies, is unknown., Methods and Results: We used empirically inspired simulation studies to explore the impact of selection bias on the marginal hazard ratio for risk of subsequent events among those with established coronary heart disease. The extent of selection bias was determined by the magnitudes of genetic and nongenetic effects on the indexing (first) coronary heart disease event. Unless the genetic hazard ratio was unrealistically large (>1.6 per allele) and assuming the sum of all nongenetic hazard ratios was <10, bias was usually <10% (downward toward the null). Despite the low bias, the probability that a confidence interval included the true effect decreased (undercoverage) with increasing sample size because of increasing precision. Importantly, false-positive rates were not affected by selection bias., Conclusions: In most empirical settings, selection bias is expected to have a limited impact on genetic effect estimates of subsequent event risk. Nevertheless, because of undercoverage increasing with sample size, most confidence intervals will be over precise (not wide enough). When there is no effect modification by history of coronary heart disease, the false-positive rates of association tests will be close to nominal., (© 2017 American Heart Association, Inc.)

HLAs are fundamental to the adaptive immune response and play critical roles in the cellular and humoral response in solid organ transplantation. The genes encoding HLA proteins are the most polymorphic within the human genome, with thousands of different allelic variants known within the population. Application of the principles of population genetics to the HLA genes has resulted in the development of a numeric metric, the calculated panel-reactive antibody (CPRA) that predicts the likelihood of a positive crossmatch as a function of a transplant candidate's unacceptable HLA antigens. The CPRA is an indispensible measure of access to transplantation for sensitized candidates and is used as the official measure of sensitization for allocation of points in the US Kidney Allocation System and Eurotransplant. Here, we review HLA population genetics and detail the mathematical basis of the CPRA. An understanding of these principles by transplant clinicians will lay the foundation for continued innovation in the care of sensitized patients.

Objective: To estimate the genetic risk conferred by known amyotrophic lateral sclerosis (ALS)-associated genes to the pathogenesis of sporadic ALS (SALS) using variant allele frequencies combined with predicted variant pathogenicity., Methods: Whole exome sequencing and repeat expansion PCR of C9orf72 and ATXN2 were performed on 87 patients of European ancestry with SALS seen at the University of Utah. DNA variants that change the protein coding sequence of 31 ALS-associated genes were annotated to determine which were rare and deleterious as predicted by MetaSVM. The percentage of patients with SALS with a rare and deleterious variant or repeat expansion in an ALS-associated gene was calculated. An odds ratio analysis was performed comparing the burden of ALS-associated genes in patients with SALS vs 324 normal controls., Results: Nineteen rare nonsynonymous variants in an ALS-associated gene, 2 of which were found in 2 different individuals, were identified in 21 patients with SALS. Further, 5 deleterious C9orf72 and 2 ATXN2 repeat expansions were identified. A total of 17.2% of patients with SALS had a rare and deleterious variant or repeat expansion in an ALS-associated gene. The genetic burden of ALS-associated genes in patients with SALS as predicted by MetaSVM was significantly higher than in normal controls., Conclusions: Previous analyses have identified SALS-predisposing variants only in terms of their rarity in normal control populations. By incorporating variant pathogenicity as well as variant frequency, we demonstrated that the genetic risk contributed by these genes for SALS is substantially lower than previous estimates., (© 2017 American Academy of Neurology.)

T-cadherin (CDH13) is an adiponectin receptor. Genome-wide association studies have identified the CDH13 gene as one of the most important candidate genes in influencing plasma adiponectin levels. Several studies recently reported single-nucleotide polymorphisms (SNPs) in CDH13 gene were associated with T2DM. The purpose of this study was to investigate the association between T2DM and 6 SNPs (rs11646213, rs12596316, rs3865188, rs12444338, rs12051272, and rs7195409) in the CDH13 gene in a Han Chinese population. A total of 674 subjects with T2DM and 588 subjects without T2DM were genotyped using the TaqMan method. Our data showed that there was an association between the SNP-rs12596316 genotype and T2DM (P < .05). Moreover, an overdominant model of inheritance showed that being an rs12596316AG heterozygote increased the risk of T2DM (P = .0041, odds ratio = 1.39; 95% confidence interval 1.11-1.73) in comparison with rs12596316AA-GG. The other 5 SNPs did not show associations with T2DM, either in the allele levels or in different inheritance models. The haplotype analysis showed that there were no associations between any haplotypes and T2DM. Our results revealed that genetic variations in the CDH13 gene were associated with T2DM susceptibility in a Han Chinese population. These results highlight the need to study the functional effects of these CDH13 gene variants in relation to the risk of developing T2DM.

Objective: ADAM17 (a disintegrin and metalloproteinase 17) is a sheddase releasing different types of membrane-bound proteins, including adhesion molecules, cytokines, and their receptors as well as inflammatory mediators. Because these substrates modulate important mechanisms of atherosclerosis, we hypothesized that ADAM17 might be involved in the pathogenesis of this frequent disease., Approach and Results: Because Adam17-knockout mice are not viable, we studied the effect of Adam17 deficiency on atherosclerosis in Adam17 hypomorphic mice (Adam17 ex/ex ), which have low residual Adam17 expression. To induce atherosclerosis, mice were crossed onto the low-density lipoprotein receptor (Ldlr)-deficient background. We found that Adam17 ex/ex .Ldlr -/- mice developed ≈1.5-fold larger atherosclerotic lesions, which contained more macrophages and vascular smooth muscle cells than wild-type littermate controls (Adam17 wt/wt .Ldlr -/- ). Reduced Adam17-mediated shedding led to significantly increased protein levels of membrane-resident TNFα (tumor necrosis factor) and TNFR2 (tumor necrosis factor receptor 2), resulting in a constitutive activation of TNFR2 signaling. At the same time, Adam17 deficiency promoted proatherosclerotic cellular functions, such as increased proliferation and reduced apoptosis in cultured macrophages and vascular smooth muscle cells and increased adhesion of macrophages to vascular endothelial cells. Because siRNA (small interfering RNA)-mediated knockdown of Tnfr2 rescued from aberrant proliferation and from misregulation of apoptosis in Adam17-depleted cells, our data indicate that TNFR2 is an important effector of ADAM17 in our mouse model., Conclusions: Our results provide evidence for an atheroprotective role of ADAM17, which might be mediated by cleaving membrane-bound TNFα and TNFR2, thereby preventing overactivation of endogenous TNFR2 signaling in cells of the vasculature., (© 2016 American Heart Association, Inc.)

Background: Truncating mutations in the giant sarcomeric gene Titin are the most common type of genetic alteration in dilated cardiomyopathy. Detailed studies have amassed a wealth of information about truncating variant position in cases and controls. Nonetheless, considerable confusion exists as to how to interpret the pathogenicity of these variants, hindering our ability to make useful recommendations to patients., Methods and Results: Building on our recent discovery of a conserved internal promoter within the Titin gene, we sought to develop an integrative statistical model to explain the observed pattern of Titin truncation variants in patients with dilated cardiomyopathy and population controls. We amassed Titin truncation mutation information from 1714 human dilated cardiomyopathy cases and >69 000 controls and found 3 factors explaining the distribution of Titin mutations: (1) alternative splicing, (2) whether the internal promoter Cronos isoform was disrupted, and (3) whether the distal C terminus was targeted (in keeping with the observation that truncation variants in this region escape nonsense-mediated decay and continue to be incorporated in the sarcomere). A model using these 3 factors had strong predictive performance with an area under the receiver operating characteristic curve of 0.81. Accordingly, individuals with either the most severe form of dilated cardiomyopathy or whose mutations demonstrated clear family segregation experienced the highest risk profile across all 3 components., Conclusions: We conclude that quantitative models derived from large-scale human genetic and phenotypic data can be applied to help overcome the ever-growing challenges of genetic data interpretation. Results of our approach can be found at http://cvri.ucsf.edu/~deo/TTNtruncationvariant.html., (© 2016 The Authors.)

Background: Congenital heart disease (CHD) is the most common type of birth defect with family- and population-based studies supporting a strong genetic cause for CHD. The goal of this study was to determine whether a whole exome sequencing (WES) approach could identify pathogenic-segregating variants in multiplex CHD families., Methods and Results: WES was performed on 9 kindreds with familial CHD, 4 with atrial septal defects, 2 with patent ductus arteriosus, 2 with tetralogy of Fallot, and 1 with pulmonary valve dysplasia. Rare variants (<1% minor allele frequency) that segregated with disease were identified by WES, and variants in 69 CHD candidate genes were further analyzed. These selected variants were subjected to in silico analysis to predict pathogenicity and resulted in the discovery of likely pathogenic mutations in 3 of 9 (33%) families. A GATA4 mutation in the transactivation domain, p.G115W, was identified in familial atrial septal defects and demonstrated decreased transactivation ability in vitro. A p.I263V mutation in TLL1 was identified in an atrial septal defects kindred and is predicted to affect the enzymatic functionality of TLL1. A disease-segregating splice donor site mutation in MYH11 (c.4599+1delG) was identified in familial patent ductus arteriosus and found to disrupt normal splicing of MYH11 mRNA in the affected individual., Conclusions: Our findings demonstrate the clinical utility of WES to identify causative mutations in familial CHD and demonstrate the successful use of a CHD candidate gene list to allow for a more streamlined approach enabling rapid prioritization and identification of likely pathogenic variants from large WES data sets., Clinical Trial Registration: URL: https://clinicaltrials.gov; Unique Identifier: NCT0112048., (© 2016 American Heart Association, Inc.)

Objective: A genetic risk score (GRS) for coronary artery disease has recently been shown to be independent of family history (FHx) in predicting future cardiovascular events. We sought to determine whether the presence of these risk factors, either individually or together, was associated with a higher burden of angiographic coronary artery disease., Approach and Results: We included 763 patients with premature acute coronary syndrome (median age, 50 [46-53] years; 30.8% women) with at least 1 major epicardial vessel stenosis enrolled in the Gender and Sex Determinants of Cardiovascular Disease From Bench to Beyond in Premature Acute Coronary Syndrome (GENESIS-PRAXY) study, a multicentre prospective cohort study of premature patients with acute coronary syndrome (aged ≤55 years). The prevalence of multivessel disease (ie, ≥2 vessels with >50% stenosis) in individuals with FHx was 49.7% as compared with 37.9% in those without FHx (P<0.01 for comparison). In adjusted models for age, sex, traditional risk factors, and GRS, FHx was associated with a higher prevalence of 3-vessel disease (odds ratio [OR], 1.42; 95% confidence interval, 0.91-2.21; P=0.12 for 2-vessel disease and OR, 2.26; 95% confidence interval, 1.29-3.95; P=0.005 for 3-vessel disease). Individuals with a high GRS were also more likely to have multivessel disease (OR, 1.41; 95% confidence interval, 1.01-1.99; P=0.047) after adjustment for traditional risk factors, including FHx. Individuals with both a FHx and a high GRS as compared with those with neither had the highest ORs for multivessel disease (adjusted OR, 2.14; 95% confidence interval, 1.24-3.69; P=0.0064)., Conclusions: In patients with premature acute coronary syndrome, the presence of either a high GRS or FHx is associated with greater severity of coronary artery disease at angiography. Whether preventive strategies targeted to genetically predisposed individuals will reduce the burden of early acute coronary syndrome warrants further study., (© 2016 American Heart Association, Inc.)

Objectives: X-ray repair cross-complementing group 1 (XRCC1) gene is an important candidate gene for influencing human cancer risks. This study examined the main and interactive effect of 9 single-nucleotide polymorphisms (SNPs) (Arg194Trp, Arg280His, Arg399Gln, c.1254C>T, c.1517G>C, c.1471G>A, C310T, 539del542, and T1915C) of XRCC1 in contribution to pancreatic cancer (PC)., Methods: A total of 298 PC patients and 298 healthy controls were enrolled. Selected SNPs in XRCC1 were genotyped. The generalized multifactor dimensionality reduction method investigated gene-gene interactions., Results: Single-locus analyses showed that, in the codominant model, the GO genotype of 539del542 might have a higher risk for PC (odds ratio [OR], 1.47; 95% confidence interval [95% CI], 1.05-2.08). For T1915C polymorphism, the TC and CC genotypes both had a higher risk for PC (OR, 1.76; 95% CI, 1.25-2.48; OR, 1.83; 95% CI, 1.05-3.19, respectively); and a similar result was observed in the dominant model (OR, 1.77; 95% CI, 1.28-2.46). A tendency of association between Arg280His and PC was also detected in the dominant model (OR, 0.70; 95% CI, 0.48-1.00). Furthermore, the generalized multifactor dimensionality reduction method showed that the 4-locus model was significant, involving Arg280His, 539del542, T1915C, and c.1517G>C (P < 0.05)., Conclusions: Thus, XRCC1 polymorphisms may contribute to the risk of PC independently or in an interactive manner.

Interferon gamma (IFN-γ) has antitumor and antiproliferative effects, and previous studies indicated IFN-γ +874T/A (rs2430561) polymorphism were related to the risk of many types of cancer. However, the association between IFN-γ +874T/A polymorphism and leukemia risk remained controversial.We performed a comprehensive meta-analysis based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement (PRISMA). Electronic database of Embase, Pubmed, and the Cochrane Library were searched for eligible articles published up to December 13, 2015. The association between genetic polymorphisms and leukemia risk was measured by odds ratios (ORs) and its corresponding 95% confidence intervals (CIs).A total of 8 studies amounting to 420 patients and 767 control subjects were retrieved for this study. Although associations between IFN-γ +874T/A polymorphism and overall leukemia risks were lacking, decreased chronic lymphocytic leukemia (CLL) risk was detected in the allelic model (T vs A, OR=0.660, 95%CI = 0.483-0.902, P = 0.009, I = 0.0% and P = 0.863 for heterogeneity), the codominant model (TT vs AA, OR = 0.472, 95%CI = 0.247-0.902, P = 0.023, I = 0.0% and P = 0.994 for heterogeneity), and dominant model (TT + TA vs AA, OR = 0.457, 95%CI = 0.285-0.734, P = 0.001, I = 40.3% and P = 0.195 for heterogeneity) by using fixed-effect model separately. On the contrary, results indicated T carries have an increased chronic myelogenous leukemia (CML) risk in dominant model (TT + TA vs AA, OR = 1.783, 95%CI = 1.236-2.573, P = 0.002, I = 19.0% and P = 0.295 for heterogeneity).This study suggests IFN-γ +874T/A polymorphism are related to CML and CLL risk. In addition, our work also points out IFN-γ +874T/A polymorphism may play dual contrasting role in leukemia risk., Competing Interests: The authors have no conflicts of interest to disclose.

Background and Aim: Genetic variants in the mammalian target of rapamycin (mTOR) gene have become an interesting topic for the study of genetic susceptibility to cancer, but their associations with the risk of gastric cancer have not been fully investigated., Materials and Methods: In a hospital-based case-control study of 1002 gastric cancer patients and 1003 cancer-free controls, we genotyped four potentially functional single nucleotide polymorphisms (SNPs) (rs1034528G>C, rs17036508T>C, rs3806317A>G, and rs2295080T>G) of mTOR and assessed their associations with the risk of gastric cancer using univariate and multivariate logistic regression analyses. We also used the multifactorial dimension reduction analysis to explore possible interactions and the false-positive report probabilities to assess significant findings., Results: We found that rs1034528 CG/CC and rs3806317 GA/GG variant genotypes were associated with an increased risk of gastric cancer under a dominant model (adjusted odds ratio=1.27 and 1.22, respectively). In the combined analysis of all four SNPs under investigation, patients with 3-4 risk genotypes of mTOR had a significantly increased risk of gastric cancer (adjusted odds ratio=1.46, 95% confidence interval=1.19-1.79) compared with those with 0-2 risk genotypes. Stratified analysis indicated that this risk was more pronounced in subgroups of men, never-smokers, never-drinkers, and clinical stages III+IV. The multifactorial dimension reduction analysis suggested some evidence of interactions between the combined genotypes and other risk factors for gastric cancer., Conclusion: These findings suggest that potentially functional SNPs of mTOR may individually or collectively contribute to the risk of gastric cancer. Larger studies with diverse ethnic populations are warranted to validate our findings.

To further elucidate the genetic underpinnings of uveal melanoma (UM) and identify new markers that correlate with disease outcome, archival formalin-fixed, paraffin-embedded enucleation specimens from 25 patients with UM and a mean follow-up of 14 years were analyzed for whole-genome copy-number alterations using OncoScan analysis. Copy-number alterations of chromosomes 1, 3, 6, and 8 were also analyzed in these tumors using multiplex ligation-dependent probe-amplification, and mutations in GNAQ, GNA11, and BAP1 were searched for by Sanger sequencing. Our study confirms the previously reported GNAQ and GNA11 mutation frequencies in UMs as well as the presence of monosomy 3 as a factor strongly indicating poor prognosis. Two cases with metastatic disease, but without monosomy of chromosome 3, showed loss of a small region in the distal part of chromosome 2p. Also, UMs leading to metastatic disease had more chromosomal aberrations than those without metastases. Three UMs lacking a GNAQ or a GNA11 mutation showed a gain of chromosome 8q; one of these cases showed extensive chromothripsis. Another case (with suspect lung metastasis) showed focal chromothripsis. Our whole-genome copy-number analysis shows that focal loss of chromosome 2p may be involved in the metastatic spread of UMs without monosomy 3; metastatic UMs carry more chromosomal aberrations than those without metastases; and chromothripsis may play a role in the oncogenesis of UMs, but does not necessarily indicate a poor prognosis. The clinical and particularly diagnostic utility of these findings needs to be corroborated in a larger set of patients with UM.

The ultrastructure of the cardiac myocyte is remarkable for the high density of mitochondria tightly packed between sarcomeres. This structural organization is designed to provide energy in the form of ATP to fuel normal pump function of the heart. A complex system comprised of regulatory factors and energy metabolic machinery, encoded by both mitochondrial and nuclear genomes, is required for the coordinate control of cardiac mitochondrial biogenesis, maturation, and high-capacity function. This process involves the action of a transcriptional regulatory network that builds and maintains the mitochondrial genome and drives the expression of the energy transduction machinery. This finely tuned system is responsive to developmental and physiological cues, as well as changes in fuel substrate availability. Deficiency of components critical for mitochondrial energy production frequently manifests as a cardiomyopathic phenotype, underscoring the requirement to maintain high respiration rates in the heart. Although a precise causative role is not clear, there is increasing evidence that perturbations in this regulatory system occur in the hypertrophied and failing heart. This review summarizes current knowledge and highlights recent advances in our understanding of the transcriptional regulatory factors and signaling networks that serve to regulate mitochondrial biogenesis and function in the mammalian heart., (© 2015 American Heart Association, Inc.)

Background: Infantile autism and schizophrenia are severe multifactorial disorders with a pronounced genetic predisposition. Their pathogeneses are often associated with oxidative stress in the brain. Previously, we established that a cell's resistance to oxidative stress depended on the copy number of transcriptionally active genes for rRNA (ribosomal genes) in the cell's genome. The feature is measured cytogenetically in cultured lymphocytes derived from patients. It varies from 120 up to 190 copies per diploid genome, with an arithmetic mean of 150±4 (SE) copies in a healthy population (n=239), being considerably lower, according to our previous results, in a sample of patients with rheumatoid arthritis (n=49), another multifactorial disease with a proven significant role of oxidative stress in its pathogenesis: from 115 to 165 copies, with a mean of 140±4 (SE). Conversely, a sample of schizophrenic patients (n=42) previously showed a higher value of copy number of active rRNA genes compared with a healthy population: from 145 to 190 copies, with a mean of 170±4. This fact is of special interest in the context of the well-known, but still unexplained phenomenon of the reduced comorbidity rate of schizophrenia and rheumatoid arthritis., Results: The copy number of active ribosomal genes was estimated in a sample of autistic children (n=51). In contrast with the schizophrenic patients studied previously, we found that the values were significantly lower than those in the healthy population: from 125 to 160 copies, with a mean of 142±5. In this work, we suggest a mathematical model of the oxidative stress dynamics on the basis of Lotka-Volterra's approach to predator-prey interactions. In our model, the 'prey' represents reactive oxygen species, whereas the 'predator' simulates molecules of the antioxidant enzymes. The rate of biosynthesis of the latter is limited by the number of ribosomes available, which, in turn, is determined by the copy number of active rRNA genes. Analysis of the model showed the existence of a unique equilibrium point that makes biological sense. The reactive oxygen species level oscillatory approaches this equilibrium value, which inversely depends on the copy number of active rRNA genes., Discussion: Our findings confirm the hypothesis of disturbance of the 'translational homeostasis' in the pathogeneses of autism and schizophrenia, and would help explain why oxidative stress markers are discovered in most autism studies, whereas similar reports related to schizophrenia are far less consistent.

Background: Endothelial growth factors including angiopoietin-2 (Ang-2), its soluble receptor Tie-2 (sTie-2), and hepatocyte growth factor play important roles in angiogenesis, vascular remodeling, local tumor growth, and metastatic potential of various cancers. Circulating levels of these biomarkers have a heritable component (between 13% and 56%), but the underlying genetic variation influencing these biomarker levels is largely unknown., Methods and Results: We performed a genome-wide association study for circulating Ang-2, sTie-2, and hepatocyte growth factor in 3571 Framingham Heart Study participants and assessed replication of the top hits for Ang-2 and sTie-2 in 3184 participants of the Study of Health in Pomerania. In multivariable-adjusted models, sTie-2 and hepatocyte growth factor concentrations were associated with single-nucleotide polymorphisms in the genes encoding the respective biomarkers (top P=2.40×10(-65) [rs2273720] and 3.64×10(-19) [rs5745687], respectively). Likewise, rs2442517 in the MCPH1 gene (in which the Ang-2 gene is embedded) was associated with Ang-2 levels (P=5.05×10(-8) in Framingham Heart Study and 8.39×10(-5) in Study of Health in Pomerania). Furthermore, single-nucleotide polymorphisms in the AB0 gene were associated with sTie-2 (top single-nucleotide polymorphism rs8176693 with P=1.84×10(-33) in Framingham Heart Study; P=2.53×10(-30) in Study of Health in Pomerania) and Ang-2 (rs8176746 with P=2.07×10(-8) in Framingham Heart Study; P=0.001 in Study of Health in Pomerania) levels on a genome-wide significant level. The top genetic loci were explained between 1.7% (Ang-2) and 11.2% (sTie-2) of the interindividual variation in biomarker levels., Conclusions: Genetic variation contributes to the interindividual variation in growth factor levels and explains a modest proportion of circulating hepatocyte growth factor, Ang-2, and Tie-2. This may potentially contribute to the familial susceptibility to cancer, a premise that warrants further studies., (© 2015 American Heart Association, Inc.)