Lοukianos S. Rallidis

The discovery of genetic loci associated with complex diseases has outpaced the elucidation of mechanisms of disease pathogenesis. Here we conducted a genome-wide association study (GWAS) for coronary artery disease (CAD) comprising 181,522 cases among 1,165,690 participants of predominantly European ancestry. We detected 241 associations, including 30 new loci. Cross-ancestry meta-analysis with a Japanese GWAS yielded 38 additional new loci. We prioritized likely causal variants using functionally informed fine-mapping, yielding 42 associations with less than five variants in the 95% credible set. Similarity-based clustering suggested roles for early developmental processes, cell cycle signaling and vascular cell migration and proliferation in the pathogenesis of CAD. We prioritized 220 candidate causal genes, combining eight complementary approaches, including 123 supported by three or more approaches. Using CRISPR-Cas9, we experimentally validated the effect of an enhancer in MYO9B, which appears to mediate CAD risk by regulating vascular cell motility. Our analysis identifies and systematically characterizes >250 risk loci for CAD to inform experimental interrogation of putative causal mechanisms for CAD.

Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of ∼185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.

To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure-related pathways and highlight tissues beyond the classical renal system in blood pressure regulation.

INTRODUCTION: Catheter ablation is potentially curative treatment for atrial fibrillation (AF). However, complications are more frequent and more severe compared with other ablation procedures. We investigated the complication rate in 1,000 AF ablation procedures in a high-volume center and examined possible risk factors. METHODS AND RESULTS: One thousand consecutive circumferential pulmonary vein radiofrequency ablations were performed for symptomatic, drug-refractory AF. Major complications were defined as the ones that were life threatening, caused permanent harm, and required intervention or prolonged hospitalization. Thirty-nine (3.9%) major periprocedural complications were observed. There was no death immediately associated with the procedure. However, there were 2 deaths (0.2%) of unclear cause, 14 days and 4 weeks after ablation. The most common complications were tamponade (1.3%), treated mainly by percutaneous drainage, and vascular complications (1.1%). There were also 4 thromboembolic events (0.4%): 3 nonfatal strokes and one transient ischemic attack. Importantly, 2 cases (0.2%) of atrial-esophageal fistula and 2 cases (0.2%) of endocarditis were observed. Factors associated with an increased complication risk were age > or = 75 years (hazard ratio 3.977, P = 0.022) and congestive heart failure (hazard ratio 5.174, P = 0.001). CONCLUSION: AF ablation still has a considerable number of major complications that may be life threatening or may lead to severe residues. Atrial-esophageal fistula is still observed despite continuous systematic methods to prevent it. Stroke, tamponade, and vascular complications are the most frequent major complications. However, in most patients treatment can be conservative and results in complete recovery. Advanced age and congestive heart failure seem to be associated with an increased risk of complications.