Citations

AbstractPrevious transcriptome‐wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome‐wide association studies (GWAS), but analyses of breast cancer subtype‐specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta‐analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER−). We further compared associations with ER+ and ER− subtypes, using a case‐only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER– breast cancer. We further identified 30 TWAS‐significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast‐cancer gene in three of six regions harboring multiple TWAS‐significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER− breast cancer.

Abstract Genetic forms of frontotemporal dementia are most commonly due to mutations in three genes, C9orf72, GRN or MAPT, with presymptomatic carriers from families representing those at risk. While cerebral blood flow shows differences between frontotemporal dementia and other forms of dementia, there is limited evidence of its utility in presymptomatic stages of frontotemporal dementia. This study aimed to delineate the cerebral blood flow signature of presymptomatic, genetic frontotemporal dementia using a voxel-based approach. In the multicentre GENetic Frontotemporal dementia Initiative (GENFI) study, we investigated cross-sectional differences in arterial spin labelling MRI-based cerebral blood flow between presymptomatic C9orf72, GRN or MAPT mutation carriers (n = 107) and non-carriers (n = 113), using general linear mixed-effects models and voxel-based analyses. Cerebral blood flow within regions of interest derived from this model was then explored to identify differences between individual gene carrier groups and to estimate a timeframe for the expression of these differences. The voxel-based analysis revealed a significant inverse association between cerebral blood flow and the expected age of symptom onset in carriers, but not non-carriers. Regions included the bilateral insulae/orbitofrontal cortices, anterior cingulate/paracingulate gyri, and inferior parietal cortices, as well as the left middle temporal gyrus. For all bilateral regions, associations were greater on the right side. After correction for partial volume effects in a region of interest analysis, the results were found to be largely driven by the C9orf72 genetic subgroup. These cerebral blood flow differences first appeared approximately 12.5 years before the expected symptom onset determined on an individual basis. Cerebral blood flow was lower in presymptomatic mutation carriers closer to and beyond their expected age of symptom onset in key frontotemporal dementia signature regions. These results suggest that arterial spin labelling MRI may be a promising non-invasive imaging biomarker for the presymptomatic stages of genetic frontotemporal dementia.

Abstract DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study (N = 1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P < 7.94 × 10−7. Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARHGAP27, and SKAP1. We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression. Significance: Identification of novel DNA methylation markers associated with EOC risk suggests that methylation at multiple CpG may affect EOC risk through regulation of gene expression.

Background: Current ischemic stroke (IS) subtyping systems are very labor-intensive and costly to implement in large samples. There is a need to develop phenotyping approaches for genetic and other studies that can be implemented using generally available items captured in electronic medical records. Objective: In this report, we seek to validate a simplified approach using results from a genetic association study. Specifically, the strength of association for known genetic signals in the NINDS Stroke Genetics Network study (SiGN) is compared between the established IS subtyping systems (TOAST and Causative Classification System (CCS) subtypes) and phenotyping based on a single item within the CCS. Methods: Non-mutually exclusive “Simple” IS subtypes were defined from single CCS items as follows: 1) Small vessel stroke- lacunar infarct on imaging (with no other imaging or other requirements); 2) large artery stroke - vascular imaging showing > 50% stenosis or <50% stenosis with plaque rupture or thrombosis judged to be due to atherosclerosis in clinically relevant artery; and 3) cardioembolic stroke - persistent or paroxysmal atrial fibrillation. We compared the GWAS signals using these definitions to the published SiGN GWAS results for TOAST and CCS, among those of European ancestry only. Results: The Table shows that, for loci significant in SiGN GWAS study, the “Simple” IS subtypes had similar strengths of association and p-values compared to results from TOAST and the causative and phenotypic CCS subtypes. Conclusions: “Simple” IS subtypes perform as well in GWAS analyses as more complex phenotyping systems and could potentially be derived through automated or semi-automated methods applied to electronic medical record systems. Since the ‘Simple” phenotypes were based on high quality CCS data, the current findings reflect optimal performance. Additional validation studies will be required for implementation in other settings.

AbstractIntroductionCatheter ablation (CA) has emerged as the preferred modality of treatment for many cardiac arrhythmias. Anatomical sites of ablation are often located in close proximity to coronary arteries. However, the incidence of CA‐related coronary injury has not been well studied. We sought to systematically evaluate all cases of CA‐related coronary injuries.Methods and ResultsA PubMed search was conducted from inception until May 1, 2017 using the keywords “coronary artery” and “ablation.” We identified 2817 published articles of which 43 articles met our inclusion criteria representing 61 cases of coronary artery injury attributed to CA procedures from 1992 to 2017. Posteroseptal accessory pathway ablation was associated with the highest incidence of coronary injury (35.6% of cases), followed by cavotricuspid isthmus‐dependent flutter (19.3%). The right coronary artery was the site of injury in over two‐thirds of all reported cases. Coronary injury was detected intraprocedurally in about half of the cases (43.1%), whereas it was a delayed presentation in the other half. Coronary intervention was performed in a third of all cases (32.7%). There were a total of three deaths attributed to coronary artery injury.ConclusionsMost (91.8%) coronary injuries are a result of anatomic proximity to the site of ablation. Awareness of the relation between coronary artery course and anatomical site of ablation could prevent myocardial damage and improve procedural safety.

Abstract Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P &lt; 2.2 × 10−6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10−7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P &lt; 1.47 × 10−3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis. Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419–30. ©2018 AACR.

AbstractBackgroundThe plantaris tendon (PT) has been implicated in the pathogenesis of symptoms in a subset of patients with Achilles region pain syndromes and traditionally has been managed via open surgical resection. Although the PT can be visualized on ultrasound, a minimally invasive technique for sonographically guided PT release has not been formally described.ObjectiveTo validate a technique to perform sonographically guided PT release in an unembalmed cadaveric model.DesignProspective, cadaveric laboratory investigation.SettingProcedural skills laboratory in a tertiary medical center.SubjectsTwenty unembalmed cadaveric knee–ankle–foot specimens (10 right, 10 left) obtained from 16 donors (6 male, 10 female) ages 55‐96 years (mean 82.6 years) with body mass indexes of 14.1‐33.2 kg/m2 (mean 23.3 kg/m2).MethodsAfter simulated local anesthesia and sonographically guided hydrodissection of the plantaris tendon–Achilles tendon interval, a single experienced operator performed sonographically guided PT release on each specimen using an in‐plane, lateral‐to‐medial approach, a commercially available, disposable 3.0‐mm hook knife, and either a 17‐5 MHz or 15‐7 MHz linear array transducer. Each specimen was subsequently dissected to assess for PT release and iatrogenic injury.Main OutcomeStatus of the PT, Achilles tendon, and regional neurovascular structures as determined by dissection.ResultsAll 20 PT releases were completed in a single attempt through a 3‐ to 5‐mm incision. Dissection confirmed complete PT release in all specimens without damage to the adjacent Achilles tendon or regional neurovascular structures.ConclusionSonographically guided PT release is technically feasible and can be performed while avoiding injury to the Achilles tendon and regional neurovascular structures. Additional research is warranted to further define the role of sonographically guided PT release in patients with suspected PT‐mediated Achilles region pain syndromes.Level of EvidenceIV

Background Sex‐specific effectiveness of rivaroxaban ( RIVA ), dabigatran ( DABI ), and warfarin in reducing myocardial infarction ( MI ), heart failure ( HF ), and all‐cause mortality among patients with atrial fibrillation are not known. We assessed sex‐specific associations of RIVA , DABI , or warfarin use with the risk of MI , HF , and all‐cause mortality among patients with atrial fibrillation. Methods and Results Medicare beneficiaries (men: 65 734 [44.8%], women: 81 135 [55.2%]) with atrial fibrillation who initiated oral anticoagulants formed the study cohort. Inpatient admissions for MI , HF , and all‐cause mortality were compared between the 3 drugs separately for men and women using 3‐way propensity‐matched samples. In men, RIVA use was associated with a reduced risk of MI admissions compared with warfarin use (hazard ratio [95% confidence interval ( CI ): 0.59 [0.38–0.91]), with a trend towards reduced risk compared with DABI use (0.67 [0.44–1.01]). In women, there were no significant differences in the risk of MI admissions across all 3 anticoagulants. In both sexes, RIVA use and DABI use were associated with reduced risk of HF admissions (men: RIVA ; 0.75 [0.63–0.89], DABI ; 0.81 [0.69–0.96]) (women: RIVA ; 0.64 [0.56–0.74], DABI ; 0.73 [0.63–0.83]) and all‐cause mortality (men: RIVA ; 0.66 [0.53–0.81], DABI ; 0.75 [0.61–0.93]) (women: RIVA ; 0.76 [0.63–0.91], DABI ; 0.77 [0.64–0.93]) compared with warfarin use. Conclusions RIVA use and DABI use when compared with warfarin use was associated with a reduced risk of HF admissions and all‐cause mortality in both sexes. However, reduced risk of MI admissions noted with RIVA use appears to be limited to men.