Levels of certain circulating short-chain dicarboxylacylcarnitine (SCDA), long-chain dicarboxylacylcarnitine (LCDA) and medium chain acylcarnitine (MCA) metabolites are heritable and predict cardiovascular disease (CVD) events. Little is known about the biological pathways that influence levels of most of these metabolites. Here, we analyzed genetics, epigenetics, and transcriptomics with metabolomics in samples from a large CVD cohort to identify novel genetic markers for CVD and to better understand the role of metabolites in CVD pathogenesis. Using genomewide association in the CATHGEN cohort (N = 1490), we observed associations of several metabolites with genetic loci. Our strongest findings were for SCDA metabolite levels with variants in genes that regulate components of endoplasmic reticulum (ER) stress (USP3, HERC1, STIM1, SEL1L, FBXO25, SUGT1) These findings were validated in a second cohort of CATHGEN subjects (N = 2022, combined p = 8.4x10-6–2.3x10-10). Importantly, variants in these genes independently predicted CVD events. Association of genomewide methylation profiles with SCDA metabolites identified two ER stress genes as differentially methylated (BRSK2 and HOOK2). Expression quantitative trait loci (eQTL) pathway analyses driven by gene variants and SCDA metabolites corroborated perturbations in ER stress and highlighted the ubiquitin proteasome system (UPS) arm. Moreover, culture of human kidney cells in the presence of levels of fatty acids found in individuals with cardiometabolic disease, induced accumulation of SCDA metabolites in parallel with increases in the ER stress marker BiP. Thus, our integrative strategy implicates the UPS arm of the ER stress pathway in CVD pathogenesis, and identifies novel genetic loci associated with CVD event risk.

changes in platelet physiology are associated with simultaneous changes in microRnA concentrations, suggesting a role for microRnA in platelet regulation. Here we investigated potential associations between microRnA and platelet reactivity (pR), a marker of platelet function, in two cohorts following a non-St elevation acute coronary syndrome (nSte-AcS) event. first, non-targeted microRnA concentrations and pR were compared in a case (n = 77) control (N = 76) cohort within the larger TRILOGY-ACS trial. MicroRNA significant in this analysis plus CVD-associated microRNAs from the literature were then quantified by targeted rt-PCR in the complete TRILOGY-ACS cohort (N = 878) and compared with matched PR samples. Finally, microRNA significant in the non-targeted & targeted analyses were verified in an independent post NSTE-ACS cohort (N = 96). From the non-targeted analysis, 14 microRNAs were associated with PR (Fold Change: 0.91-1.27, p-value: 0.004-0.05). From the targeted analysis, five microRNAs were associated with PR (Beta: −0.09-0.22, p-value: 0.004-0.05). Of the 19 significant microRNAs, three, miR-15b-5p, miR-93 and miR-126, were consistently associated with pR in the tRiLoGY-AcS and independent Singapore post-AcS cohorts, suggesting the measurement of circulating microRnA concentrations may report on dynamic changes in platelet biology following a cardiovascular ischemic event.Despite advancements in its management, cardiovascular disease including non-ST elevation acute coronary syndrome (NSTE-ACS) remains a major cause of patient morbidity and mortality 1-4 . Antiplatelet therapies including P2Y 12 antagonists are used to treat NSTE-ACS acutely and in the longer-term. While measurements of platelet reactivity (PR) have facilitated the rapid quantification of anti-platelet medication efficacy, questions still remain about the utility of PR to predict clinical outcomes 5-8 . Platelet genetics and PR sub-studies from large-scale clinical trials have informed our understanding of individual variability in P2Y 12 inhibitor response, but genomic regulation of individual patient's PR has not been fully clarified 9-14 .Small non-coding ribonucleic acids (RNA) including microRNAs have emerged as potential regulators of PR in patients with cardiovascular disease 15 . MicroRNAs (miRNAs) are 18-22 nucleotide non-coding RNAs that play an essential role in gene modulation and expression and are established regulators of cardiovascular

Objective Matrix metalloproteinase-9 (MMP-9) is a protease associated with degradation of collagen and elastin. Because increased MMP-9 activity in vaginal tissue has been associated with pelvic organ prolapse, we sought to comprehensively estimate MMP-9 genetic variants and the risk for advanced prolapse. Methods This is a candidate gene association study of women with stage III-IV prolapse (cases, n=239) and women with stage 0-1 prolapse (controls, n=197). We attempted to oversample “extreme” phenotypes, including younger women with severe prolapse and older women without prolapse, in an attempt to concentrate the genetic effect. We utilized a linkage disequilibrium tagged approach to identify single nucleotide polymorphisms (SNPs) in MMP-9 to evaluate in our study. In order to minimize potential confounding by race, our analysis focused on non-Hispanic white women. We performed multivariable logistic regression to estimate the association between MMP-9 SNPs and case-control status, adjusting for age and vaginal parity. Results Women with advanced prolapse were slightly younger (64.8 ± 10.3 vs 69.0 ± 10.2 years, p=<0.001) and more likely to have had one or more vaginal deliveries (96.6% vs 82.2%, p<0.001) when compared to controls. Eight SNPs were assessed, which represented 93% coverage of the MMP-9 gene. Of these, two were associated with advanced prolapse: 1) rs3918253 (adjusted OR 0.64 [95% CI 0.41, 1.0], p=0.05) and 2) rs3918256 (adjusted OR 0.64 [95% CI 0.41, 1.01], p=0.05). Conclusions Matrix metalloproteinase-9 (MMP-9) is a biologically-plausible candidate gene for pelvic organ prolapse given our results.