Shared genetic etiology of vessel diseases: A genome-wide multi-traits association analysis.

BACKGROUND: The comorbidity among vascular diseases has been widely reported, however, the contribution of shared genetic components remains ambiguous. METHODS: Based on genome-wide association study summary statistics, we employed statistical genetics methodologies to explore the shared genetic basis of eight vascular diseases: coronary artery disease, abdominal aortic aneurysm, ischemic stroke, peripheral artery disease, thoracic aortic aneurysm, phlebitis, varicose veins, and venous thromboembolism. We assessed global and local genetic correlations among these disorders by linkage disequilibrium score regression, high-definition likelihood, and local analysis of variant association. Cross-trait analyses conducted with CPASSOC identified pleiotropic variants and loci. Further, biological pathways at the multi-omics level were explored using multimarker analysis of genomic annotation, transcriptome-wide and proteome-wide association studies. Causal associations among the vascular diseases were evaluated by mendelian randomization and latent causal variable to assess vertical pleiotropic effects. RESULTS: We found significant global genetic associations in 18 pairs of vascular diseases. Additionally, we discovered 317 unique genomic regions where at least one pair of traits demonstrated significant correlation. Multi-trait association analysis identified 19,361 significant potential pleiotropic variants in 274 independent pleiotropic loci. Multi-trait colocalization analysis revealed 56 colocalized loci in specific disease sets. Gene-based analysis identified 700 potential pleiotropic genes, which were subsequently validated at both transcriptome and protein levels. Gene-set enrichment analysis supports the role of biological pathways such as vessel wall structure, coagulation and lipid transport in vascular disease. Additionally, 7 pairs of vascular diseases have a causal relationship. CONCLUSIONS: Our study indicates a shared genetic basis and the presence of common risk genes among vascular diseases. These findings offer novel insights into potential mechanisms underlying the association between vascular diseases, as well as provide guidance for interventions and treatments of multi-vascular conditions.

VENOARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION REDUCES MYOCARDIAL AND MITOCHONDRIAL DAMAGE IN ACUTE MYOCARDIAL INFARCTION.

ABSTRACT: Background: Myocardial infarction (MI) is a common cardiovascular disease with a high fatality rate once accompanied by cardiogenic shock. The efficacy of extracorporeal membrane oxygenation (ECMO) in treating MI is controversial. Methods: MI was induced by ligating the left anterior descending artery (LAD) in adult male rats. Groups were defined as follows: MI group, reperfusion for 90 min after 30 min of LAD occlusion; MI + ECMO group, reperfusion and ECMO were performed for 90 min immediately after 30 min of LAD occlusion; prolonged MI + ECMO group, ECMO was used immediately after 30 min of occlusion with persistent occlusion of the LAD for an additional 30 min, followed by 90 min of reperfusion. The myocardial infarct size and mitochondrial morphology and function data were collected and compared of each group. Results: The ECMO groups had a smaller myocardial infarct size and larger percentage ejection fraction. Compared with the prolonged MI + ECMO group, the immediate reperfusion group had a lower percentage of infarct size (63.28% vs. 17.97% vs. 31.22%, MI vs. MI + ECMO vs. prolonged MI + ECMO). Mitochondria isolated from the ischemic zone showed an intact mitochondrial structure, including fewer voids and broken cristae, and preserved activity of mitochondrial complex II and complex IV in ECMO groups. Conclusions: ECMO support in MI can reduce myocardial injury despite delayed coronary reperfusion.

The Role of Inflammatory Biomarkers in Mediating the Effect of Inflammatory Bowel Disease on nonmalignant Digestive System Diseases: A Multivariable Mendelian Randomized Study.

Background: While observation studies have shown a positive correlation between inflammatory bowel disease (IBD) and the risk of nonmalignant digestive system diseases, a definitive causal relationship has not yet been clearly established. Methods: Mendelian randomization (MR) was employed to investigate the potential causal association between genetic susceptibility to IBD and nonmalignant gastrointestinal diseases. Genetic variants were extracted as instrumental variables (IVs) from a genome-wide association study (GWAS) meta-analysis, which included 12,194 cases of Crohn's disease (CD) and 28,072 control cases of European ancestry. The GWAS for ulcerative colitis (UC) included 12,366 UC and 33,609 control cases of European ancestry. All IVs reached genome-wide significance (GWAS p value <5 × 10-8). Summary-level data for acute pancreatitis (AP), irritable bowel syndrome (IBS), gastroesophageal reflux disease, cholelithiasis, and CeD (celiac disease) were obtained from the GWAS meta-analysis and the FinnGen dataset. Summary-level data on relevant inflammatory factors were provided by the International Genetic Consortium. Univariate MR analysis was conducted using inverse variance weighting as the primary method for estimating causal effects. Multivariate MR analyses were also performed to detect possible mediators. Results: Genetic susceptibility to UC was associated with an increased risk of AP (OR = 1.08; 95% CI = 1.03-1.13; p=0.002) and IBS odds ratio (OR] = 1.07; 95% confidence interval (CI] = 1.03-1.11; (p < 0.001). In terms of potential mediators, interleukin 6 (IL-6) had a driving effect on the association between UC and AP. There was no apparent evidence of increased risk with CD. Meanwhile, genetic susceptibility to CD increases the risk of CeD (OR = 1.14; 95% CI = 1.03-1.25; p=0.01). Conclusions: The evidence suggests that UC is associated with an elevated risk of AP and IBS, and IL-6 may be responsible in AP. CD is associated with an increased risk of developing CeD. Implementing a proactive monitoring program for assessing the risk of gastrointestinal diseases in UC patients, particularly those with elevated IL-6 levels, may be of interest. In addition, the presence of AP and IBS may indicate the presence of UC. Preventing CeD is an essential consideration in the therapeutic management of patients with CD.