Integrating Genome-Wide Genetic Variations and Monocyte Expression Data Reveals Trans-Regulated Gene Modules in Humans

One major expectation from the transcriptome in humans is to characterize the biological basis of associations identified by genome-wide association studies. So far, few cis expression quantitative trait loci (eQTLs) have been reliably related to disease susceptibility. Trans-regulating mechanisms may play a more prominent role in disease susceptibility. We analyzed 12,808 genes detected in at least 5% of circulating monocyte samples from a population-based sample of 1,490 European unrelated subjects. We applied a method of extraction of expression patterns—independent component analysis—to identify sets of co-regulated genes. These patterns were then related to 675,350 SNPs to identify major trans-acting regulators. We detected three genomic regions significantly associated with co-regulated gene modules. Association of these loci with multiple expression traits was replicated in Cardiogenics, an independent study in which expression profiles of monocytes were available in 758 subjects. The locus 12q13 (lead SNP rs11171739), previously identified as a type 1 diabetes locus, was associated with a pattern including two cis eQTLs, RPS26 and SUOX, and 5 trans eQTLs, one of which (MADCAM1) is a potential candidate for mediating T1D susceptibility. The locus 12q24 (lead SNP rs653178), which has demonstrated extensive disease pleiotropy, including type 1 diabetes, hypertension, and celiac disease, was associated to a pattern strongly correlating to blood pressure level. The strongest trans eQTL in this pattern was CRIP1, a known marker of cellular proliferation in cancer. The locus 12q15 (lead SNP rs11177644) was associated with a pattern driven by two cis eQTLs, LYZ and YEATS4, and including 34 trans eQTLs, several of them tumor-related genes. This study shows that a method exploiting the structure of co-expressions among genes can help identify genomic regions involved in trans regulation of sets of genes and can provide clues for understanding the mechanisms linking genome-wide association loci to disease

Short-Term Outcomes of Tricuspid Edge-to-Edge Repair in Clinical Practice.

BACKGROUND Severe tricuspid regurgitation (TR) is known to be associated with substantial morbidity and mortality. OBJECTIVES The authors sought to study the acute outcomes of subjects treated by tricuspid transcatheter edge-to-edge repair with the TriClip system (Abbott) in a contemporary, real-world setting. METHODS The bRIGHT (An Observational Real-World Study Evaluating Severe Tricuspid Regurgitation Patients Treated With the Abbott TriClip™ Device) postapproval study is a prospective, single-arm, open-label, multicenter, postmarket registry conducted at 26 sites in Europe. Echocardiographic assessment was performed at a core laboratory. RESULTS Enrolled subjects were elderly (79 ± 7 years of age) with significant comorbidities. Eighty-eight percent had baseline massive or torrential TR, and 80% of subjects were in NYHA functional class III or IV. Successful device implantation occurred in 99% of subjects, and TR was reduced to ≤moderate at 30 days in 77%. Associated significant improvements in NYHA functional class (I/II, 20% to 79%; P < 0.0001) and Kansas City Cardiomyopathy Questionnaire score (19 ± 23 points improvement; P < 0.0001) were observed at 30 days. With baseline TR grade removed as a variable, smaller right atrial volume and smaller tethering distance at baseline were independent predictors of TR reduction to ≤moderate at discharge (OR: 0.679; 95% CI: 0.537-0.858; P = 0.0012; OR: 0.722; 95% CI: 0.564-0.924; P = 0.0097). Fourteen subjects (2.5%) experienced a major adverse event at 30 days. CONCLUSIONS Transcatheter tricuspid valve repair was found to be safe and effective in treating significant TR in a diverse, real-world population. (An Observational Real-World Study Evaluating Severe Tricuspid Regurgitation Patients Treated With the Abbott TriClip™ Device [bRIGHT]; NCT04483089)