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CYP17A1 is a cytochrome P450 enzyme that has 17-alpha-hydroxylase and C17,20-lyase activities. Cyp17a11 deficiency is associated with high body mass and visceral fat deposition in atherosclerotic female ApoE knockout (KO, d/d or −/−) mice. In the present study, we aimed to investigate the effects of diet and Cyp17a1 genotype on the gut microbiome. Female Cyp17a1 (d/d) × ApoE (d/d) (DKO) and ApoE (d/d) (controls) were fed either standard chow or a Western-type diet (WTD), and we demonstrated the effects of genetics and diet on the body mass of the mice and composition of their gut microbiome. We found a significantly lower alpha diversity after accounting for the ecological network structure in DKO mice and WTD-fed mice compared with chow-fed ApoE(d/d). Furthermore, we found a strong significant positive association of the Firmicutes vs. Bacteroidota ratio with body mass and the circulating total cholesterol and triglyceride concentrations of the mice when feeding the WTD, independent of the Cyp17a1 genotype. Further pathway enrichment and network analyses revealed a substantial effect of Cyp17a1 genotype on associated cardiovascular and obesity-related pathways involving aspartate and L-arginine. Future studies are required to validate these findings and further investigate the role of aspartate/L-arginine pathways in the obesity and body fat distribution in our mouse model.

Two private, heterozygous mutations in two functionally related genes, GUCY1A3 and CCT7 , are identified in an extended family with myocardial infarction; these genes encode proteins that work together to inhibit platelet activation after nitric oxide stimulation, suggesting a link between impaired nitric oxide signalling and myocardial infarction risk. Signal failure raises cardiac disease risk Next-generation sequencing in families with multiple affected individuals has revolutionized the identification of rare and private (single family or limited group) mutations. Here, the authors identify two private, heterozygous mutations in two functionally related genes, GUCY1A3 and CCT7 , in an extended family with myocardial infarction. The products of these genes work together to induce vasodilation and inhibit platelet activation upon stimulation with nitric oxide. Starting with a severely affected family, this work identifies a link between impaired nitric oxide signalling and myocardial infarction risk, possibly through accelerated thrombus formation. Reversal of this signalling defect may provide a new therapeutic strategy for reducing the risk of myocardial infarction. Myocardial infarction, a leading cause of death in the Western world 1 , usually occurs when the fibrous cap overlying an atherosclerotic plaque in a coronary artery ruptures. The resulting exposure of blood to the atherosclerotic material then triggers thrombus formation, which occludes the artery 2 . The importance of genetic predisposition to coronary artery disease and myocardial infarction is best documented by the predictive value of a positive family history 3 . Next-generation sequencing in families with several affected individuals has revolutionized mutation identification 4 . Here we report the segregation of two private, heterozygous mutations in two functionally related genes, GUCY1A3 (p.Leu163Phefs*24) and CCT7 (p.Ser525Leu), in an extended myocardial infarction family. GUCY1A3 encodes the α1 subunit of soluble guanylyl cyclase (α1-sGC) 5 , and CCT7 encodes CCTη, a member of the tailless complex polypeptide 1 ring complex 6 , which, among other functions, stabilizes soluble guanylyl cyclase. After stimulation with nitric oxide, soluble guanylyl cyclase generates cGMP, which induces vasodilation and inhibits platelet activation 7 . We demonstrate in vitro that mutations in both GUCY1A3 and CCT7 severely reduce α1-sGC as well as β1-sGC protein content, and impair soluble guanylyl cyclase activity. Moreover, platelets from digenic mutation carriers contained less soluble guanylyl cyclase protein and consequently displayed reduced nitric-oxide-induced cGMP formation. Mice deficient in α1-sGC protein displayed accelerated thrombus formation in the microcirculation after local trauma. Starting with a severely affected family, we have identified a link between impaired soluble-guanylyl-cyclase-dependent nitric oxide signalling and myocardial infarction risk, possibly through accelerated thrombus formation. Reversing this defect may provide a new therapeutic target for reducing the risk of myocardial infarction.

Background Circulating microRNAs (miRNAs) emerge as novel biomarkers in cardiovascular diseases. Diagnosing acute pulmonary embolism (PE) remains challenging due to a diverse clinical presentation and the lack of specific biomarkers. Here we evaluate serum miRNAs as potential biomarkers in acute PE. Methods We enrolled 30 patients with acute, CT (computed tomography)-angiographically confirmed central PE and collected serum samples on the day of emergency room admission (1st day) and from 22 of these patients 9 months thereafter. For comparison, we examined serum samples from patients with acute non ST-segment elevation myocardial infarction (NSTEMI, n = 30) and healthy individuals (n = 12). Results We randomly selected 16 out of 30 PE patients and screened sera from the acute (1st day) and chronic stages (9 months) for 754 miRNAs using microarrays and found 37 miRNAs to be differentially regulated. Across all miRNAs, miRNA-1233 displayed the highest fold change (FC) from acute to chronic stage (log 2 FC 11.5, p < 0.004). We validated miRNA-1233 by real-time quantitative polymerase chain reaction (RT-qPCR). In acute PE (1st day) we found elevated levels of miRNA-1233 in comparison to NSTEMI (log 2 FC 5.7, p < 0.0001) and healthy controls (log 2 FC 7.7, p < 0.0001). miRNA-1233 differentiated acute PE from NSTEMI patients and healthy individuals with 90 and 90 % sensitivity, and 100 and 92 % specificity [area under the curve (AUC) 0.95, p < 0.001 and 0.91, p < 0.001], respectively. Conclusions This is the first report that identifies a miRNA that allows distinguishing acute PE from acute NSTEMI and healthy individuals with high specificity and sensitivity.

Jeanette Erdmann and colleagues identify a locus on chromosome 3q22.3 associated with coronary artery disease. The SNP with the strongest association is in MRAS , which encodes a membrane-anchored GTP-binding protein. We present a three-stage analysis of genome-wide SNP data in 1,222 German individuals with myocardial infarction and 1,298 controls, in silico replication in three additional genome-wide datasets of coronary artery disease (CAD) and subsequent replication in ∼25,000 subjects. We identified one new CAD risk locus on 3q22.3 in MRAS ( P = 7.44 × 10 −13 ; OR = 1.15, 95% CI = 1.11–1.19), and suggestive association with a locus on 12q24.31 near HNF1A-C12orf43 ( P = 4.81 × 10 −7 ; OR = 1.08, 95% CI = 1.05–1.11).

Coronary artery disease (CAD) and myocardial infarction (MI) have a genetic basis, but the precise genetic underpinning remains controversial. Recently, an association of the LRP8 R952Q polymorphism (rs5174) with familial premature CAD/MI was reported. We analysed rs5174 (or the perfect proxy rs5177) in 1,210 patients with familial MI and 1,015 controls from the German MI Family study, in 1,926 familial CAD (1,377 with MI) patients and 2,938 controls from the Wellcome Trust Case Control Consortium (WTCCC) MI/CAD cohort, in 346 CAD patients and 351 controls from the AtheroGene study and in 295 men with incident CAD and 301 controls from the Prospective Epidemiological Study of MI study and found no evidence for association in any of the populations studied. In the WTCCC and the German MI Family studies, additional single-nucleotide polymorphisms in the LRP8 gene were analysed and displayed no evidence for association either.