Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.</p

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

Predictors of outcome after alcohol septal ablation in patients with hypertrophic obstructive cardiomyopathy. Special interest for the septal coronary anatomy

<p>Alcohol septal ablation (ASA) provides symptomatic relief in most but not all patients with hypertrophic obstructive cardiomyopathy (HOCM). Therefore we investigated predictors of outcome after ASA.</p><p>Clinical, echocardiographic, angiographic and procedural characteristics were analysed in 113 consecutive patients. Successful ASA was defined as NYHA a parts per thousand currency signaEuro parts per thousand 2 with improvement of at least 1 class combined with a resting gradient <30 mmHg and provoked gradient <50 mmHg at 4-month follow-up.</p><p>In 37 patients ASA was not successful. In multivariate analysis, baseline gradient (OR 1.06 (1.01-1.11) per 5 mmHg, p = 0.024) and distance to the ablated septal branch (OR 1.09 (1.03-1.16) per mm, p = 0.004) were predictors of unsuccessful outcome. The combined presence of a non-ablated septal branch and a distance a parts per thousand yenaEuro parts per thousand 19 mm to the ablated branch was a predictor of unsuccessful outcome (OR 5.88 (2.06-16.7), p <0.001).</p><p>Baseline gradient and a greater distance from the origin of the left anterior descending artery to the ablated septal branch combined with a non-ablated proximal septal branch are associated with an unsuccessful outcome after ASA.</p>

Prevalência e características associadas à síndrome metabólica em nipo-brasileiros com e sem doença periodontal Prevalence and characteristics associated with metabolic syndrome in Japanese-Brazilians with and without periodontal disease

Verificou-se, num estudo transversal, a relação entre as doenças periodontais e a síndrome metabólica. Foram analisados dados de 1.315 nipo-brasileiros com idade entre 30 e 92 anos. Os indivíduos foram submetidos a exames físicos, odontológicos e laboratoriais. Os dados foram descritos através de médias e porcentagens e a associação entre as variáveis foi verificada por meio de regressão logística. Do total de sujeitos examinados, 215 (16,4%) apresentaram higidez periodontal, 484 (36,8%) edentulismo total, 513 (39%) gengivites, 85 (6,5%) periodontite inicial ou moderada e 18 (1,4%) periodontite avançada. A prevalência de síndrome metabólica entre os nipo-brasileiros foi 54,3%, e apesar de esta ter sido maior entre os que apresentaram periodontites quando comparados aos sem nenhum comprometimento da saúde bucal (51,5% vs. 48,8%) essa associação não foi estatisticamente significante. Neste estudo os indivíduos com síndrome metabólica se caracterizaram por pior perfil antropométrico e metabólico.<br>This cross-sectional study focused on the relationship between periodontal disease and metabolic syndrome. Data were analyzed from 1,315 Japanese-Brazilians ranging from 30 to 92 years of age, submitted to physical, laboratory, and dental exams. Means and percentages were used in the data description and logistic regression pattern in the analysis of associations among variables. 484 (36.8%) of the 1,315 were edentulous, 215 (16.4%) enjoyed periodontal health, 513 (39%) had gingivitis, 85 (6.5%), showed initial or moderate periodontitis, and 18 (1.4%) suffered from chronic periodontits. Prevalence of metabolic syndrome was 54.3%, higher among individuals with periodontitis than in the healthy (51.5% vs. 48.8%), but this association was not statistically significant. Individuals with metabolic syndrome showed a worse metabolic and anthropometric profile

Microbiome and diseases: colorectal cancer

Cancers of the large intestine are among the most frequent malignomas worldwide and also rank among the most frequent causes for cancer-related mortality in developed countries, with an even increasing incidence in an aging population. Patient survival and treatment options in the metastatic form of this disease are still relatively poor. The cell-autonomous genetic and epigenetic changes associated with carcinogenesis, and the stepwise and consecutive progression along the adenoma-carcinoma sequence in the colorectum, have been studied intensively over the last decades. However, there is a growing interest in the impact of gut microbial communities on the initiation and progression of this cancer entity. Overwhelming evidence meanwhile suggests that the microbiota is an important and potentially causative factor for colorectal cancer (CRC). A disturbance in the microbial community may lead to impairment of epithelial barrier function, imbalance in epithelial self-renewal, DNA damage, and altered immune responses, thereby fostering tumor initiation and progression

Microbiome and Diseases: Colorectal Cancer

Cancers of the large intestine are among the most frequent malignomas worldwide and also rank among the most frequent causes for cancer-related mortality in developed countries, with an even increasing incidence in an aging population. Patient survival and treatment options in the metastatic form of this disease are still relatively poor. The cell-autonomous genetic and epigenetic changes associated with carcinogenesis, and the stepwise and consecutive progression along the adenoma-carcinoma sequence in the colorectum, have been studied intensively over the last decades. However, there is a growing interest in the impact of gut microbial communities on the initiation and progression of this cancer entity. Overwhelming evidence meanwhile suggests that the microbiota is an important and potentially causative factor for colorectal cancer (CRC). A disturbance in the microbial community may lead to impairment of epithelial barrier function, imbalance in epithelial self-renewal, DNA damage, and altered immune responses, thereby fostering tumor initiation and progression

Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease.

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P 64 1 7 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 7 10(-17); including ADGC data, meta P = 5.0 7 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 7 10(-14); including ADGC data, meta P = 1.2 7 10(-16)) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 7 10(-4); including ADGC data, meta P = 8.6 7 10(-9)), CD33 (GERAD+, P = 2.2 7 10(-4); including ADGC data, meta P = 1.6 7 10(-9)) and EPHA1 (GERAD+, P = 3.4 7 10(-4); including ADGC data, meta P = 6.0 7 10(-10))