Impact of genetic variation on perioperative bleeding.
Ontology highlight
ABSTRACT:
SUBMITTER: Muehlschlegel JD
PROVIDER: S-EPMC5266599 | biostudies-literature | 2008 Sep
REPOSITORIES: biostudies-literature
Publications
Impact of genetic variation on perioperative bleeding.
Muehlschlegel Jochen D JD Body Simon C SC
American journal of hematology 20080901 9
Variation in bleeding in the perioperative period is a complex and multifactorial event associated with immediate and delayed consequences for the patient and health care resources. Little is known about the complex genetic influences on perioperative bleeding. With the discovery of multiple variations in the human genome and ever-growing databases of well-phenotyped surgical patients, better identification of patients at risk of bleeding is becoming a reality. In this review, polymorphisms in t ...[more]
Similar Datasets
Project description:Background Fish oil is among the most common natural supplements for treatment of hypertriglyceridemia or prevention of cardiovascular disease. However, concerns about theoretical bleeding risk have led to recommendations that patients should stop taking fish oil before surgery or delay in elective procedures for patients taking fish oil by some health care professionals. Methods and Results We tested the effect of fish oil supplementation on perioperative bleeding in a multinational, placebo-controlled trial involving 1516 patients who were randomized to perioperative fish oil (eicosapentaenoic acid+docosahexaenoic acid; 8-10 g for 2-5 days preoperatively, and then 2 g/d postoperatively) or placebo. Primary outcome was major perioperative bleeding as defined by the Bleeding Academic Research Consortium. Secondary outcomes include perioperative bleeding per thrombolysis in myocardial infarction and International Society on Thrombosis and Hemostasis definitions, chest tube output, and total units of blood transfused. Participants' mean (SD) age was 63 (13) years, and planned surgery included coronary artery bypass graft (52%) and valve surgery (50%). The primary outcome occurred in 92 patients (6.1%). Compared with placebo, risk of Bleeding Academic Research Consortium bleeding was not higher in the fish oil group: odds ratio, 0.81; 95% CI, 0.53-1.24; absolute risk difference, 1.1% lower (95% CI, -3.0% to 1.8%). Similar findings were seen for secondary bleeding definitions. The total units of blood transfused were significantly lower in the fish oil group compared with placebo (mean, 1.61 versus 1.92; P<0.001). Evaluating achieved plasma phospholipid omega-3 polyunsaturated fatty acids levels with supplementation (on the morning of surgery), higher levels were associated with lower risk of Bleeding Academic Research Consortium bleeding, with substantially lower risk in the third (odds ratio, 0.30 [95% CI, 0.11-0.78]) and fourth (0.36 [95% CI, 0.15-0.87]) quartiles, compared with the lowest quartile. Conclusions Fish oil supplementation did not increase perioperative bleeding and reduced the number of blood transfusions. Higher achieved n-3-PUFA levels were associated with lower risk of bleeding. These novel findings support the need for reconsideration of current recommendations to stop fish oil or delay procedures before cardiac surgery. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT00970489.
| S-EPMC6376981 | biostudies-literature
Project description:BackgroundVon Willebrand factor (vWF) is an important part of blood coagulation since it binds platelets to each other and to endothelial cells. In traumatic and surgical haemorrhage, both blood cells and plasmatic factors are consumed, leading to consumption coagulopathy and fluid resuscitation. This often results in large amounts of crystalloids and blood products being infused. Additional administration of vWF complex and platelets might mitigate this problem. We hypothesize that administration of vWF concentrate additionally to platelet concentrates reduces blood loss and the amount of blood products (platelets, red blood cells [RBC], fresh frozen plasma [FFP]) administered.MethodsWe conducted a monocentric 6-year retrospective data analysis of cardiac surgery patients. Included were all patients receiving platelet concentrates within 48 h postoperatively. Patients who additionally received vWF concentrates were allocated to the intervention group and all others to the control group. Groups were compared in mixed regression models correcting for known confounders, based on nearest neighbour propensity score matching. Primary endpoints were loss of blood (day one and two) and amount of needed blood products on day one and two (platelets, RBC, FFP). Secondary endpoints were intensive care unit (ICU) and in-hospital length of stay, ICU and in-hospital mortality, and absolute difference of platelet counts before and after treatment.ResultsOf 497 patients analysed, 168 (34%) received vWF concentrates. 121 patients in both groups were considered for nearest neighbour matching. Patients receiving additional vWF were more likely to receive more blood products (RBC, FFP, platelets) in the first 24 h after surgery and had around 200 mL more blood loss at the same time.ConclusionIn this retrospective analysis, no benefit in additional administration of vWF to platelet concentrates on perioperative blood loss, transfusion requirement (platelets, RBC, FFP), length of stay, and mortality could be found. These findings should be verified in a prospective randomized controlled clinical trial (www.clinicaltrials.gov identifier NCT04555785).
| S-EPMC10836859 | biostudies-literature
Project description:Prothrombin complex concentrates (PCCs) contain vitamin K-dependent clotting factors (II, VII, IX, and X) and are marketed as 3 or 4 factor-PCC formulations depending on the concentrations of factor VII. PCCs rapidly restore deficient coagulation factor concentrations to achieve hemostasis, but like with all procoagulants, the effect is balanced against thromboembolic risk. The latter is dependent on both the dose of PCCs and the individual patient prothrombotic predisposition. PCCs are approved by the US Food and Drug Administration for the reversal of vitamin K antagonists in the setting of coagulopathy or bleeding and, therefore, can be administered when urgent surgery is required in patients taking warfarin. However, there is growing experience with the off-label use of PCCs to treat patients with surgical coagulopathic bleeding. Despite their increasing use, there are limited prospective data related to the safety, efficacy, and dosing of PCCs for this indication. PCC administration in the perioperative setting may be tailored to the individual patient based on the laboratory and clinical variables, including point-of-care coagulation testing, to balance hemostatic benefits while minimizing the prothrombotic risk. Importantly, in patients with perioperative bleeding, other considerations should include treating additional sources of coagulopathy such as hypofibrinogenemia, thrombocytopenia, and platelet disorders or surgical sources of bleeding. Thromboembolic risk from excessive PCC dosing may be present well into the postoperative period after hemostasis is achieved owing to the relatively long half-life of prothrombin (factor II, 60-72 hours). The integration of PCCs into comprehensive perioperative coagulation treatment algorithms for refractory bleeding is increasingly reported, but further studies are needed to better evaluate the safe and effective administration of these factor concentrates.
| S-EPMC4840070 | biostudies-literature
Project description:Von Willebrand disease (VWD) is an inherited bleeding disorder that often manifests clinically with hemorrhage after invasive procedures. We investigated the association between a diagnosis of VWD and bleeding and thrombotic outcomes following major non-cardiac surgery in a large national database from the United States. Patients age ≥45 years requiring major non-cardiac surgery were identified from Healthcare Cost and Utilization Project's National Inpatient Sample data. Von Willebrand disease, perioperative major adverse cardiovascular events (MACE), thrombotic events, and hemorrhage were defined by ICD9 diagnosis codes. From 2004 to 2013, a total of 10,581,621 hospitalizations for major non-cardiac surgery met study inclusion criteria and VWD was identified in 3765 (0.036%). In adjusted analyses, patients with VWD were significantly more likely to develop post-operative hemorrhage than patients without VWD (5.5 vs. 1.9%, p < 0.001; adjusted OR 3.49, 95% CI 3.03-4.03), but had similar odds of perioperative MACE and thrombotic events. Thus, a diagnosis of VWD was associated with increased risks of bleeding with non-cardiac surgery, without a corresponding reduction in perioperative thrombosis in comparison to patients without VWD. Perioperative management of patients with hereditary bleeding disorders and mitigation of thrombotic risks requires further study.
| S-EPMC5515288 | biostudies-literature
Project description:Genetic variants that disrupt polyadenylation can cause or contribute to genetic disorders. Yet, due to the complex cis-regulation of polyadenylation, variant interpretation remains challenging. Here, we introduce a residual neural network model, APARENT2, that can infer 3’-cleavage and polyadenylation from DNA sequence more accurately than any previous model. This model generalizes to the case of alternative polyadenylation (APA) for a variable number of polyadenylation signals. We demonstrate APARENT2’s performance on several variant datasets, including functional reporter data and human 3’ aQTLs from GTEx. We apply neural network interpretation methods to gain insights into disrupted or protective higher-order features of polyadenylation. We fine-tune APARENT2 on human tissue-resolved transcriptomic data to elucidate tissue-specific variant effects. By combining APARENT2 with models of mRNA stability, we extend aQTL effect size predictions to the entire 3’ untranslated region. Finally, we perform in-silico saturation mutagenesis of all human polyadenylation signals and compare the predicted effects of >44 million variants against gnomAD. While loss-of-function variants were generally selected against, we also find specific clinical conditions linked to gain-of-function mutations. For example, we detect an association between gain-of-function mutations in the 3’-end and Autism Spectrum Disorder. To experimentally validate APARENT2’s predictions, we assayed clinically relevant variants in multiple cell lines, including microglia-derived cells. References and variant APA libraries were cloned into a reporter. APA profiling data was obtained from RNA-seq of 3 different cell lines (HEK293T, SK-N-SH, and HMC3) with 2 replicates of each library. Polyadenylation cleavage position was determined for mapped reads, and then UMIs were collapsed to determine measured variant log odds ratio of cleavage.
2022-10-08 | GSE214825 | GEO
Project description:The CRISPR-CRISPR-associated (Cas) nuclease system offers the ability to perform unprecedented functional genetic experiments and the promise of therapy for a variety of genetic disorders. The understanding of factors contributing to CRISPR targeting efficacy and specificity continues to evolve. As CRISPR systems rely on Watson-Crick base pairing to ultimately mediate genomic cleavage, it logically follows that genetic variation would affect CRISPR targeting by increasing or decreasing sequence homology at on-target and off-target sites or by altering protospacer adjacent motifs. Numerous efforts have been made to document the extent of human genetic variation, which can serve as resources to understand and mitigate the effect of genetic variation on CRISPR targeting. Here, we review efforts to elucidate the effect of human genetic variation on CRISPR targeting at on-target and off-target sites with considerations for laboratory experiments and clinical translation of CRISPR-based therapies.
| S-EPMC6319324 | biostudies-literature
Project description:Current human sequencing projects observe an abundance of extremely rare genetic variation, suggesting recent acceleration of population growth. To better understand the impact of such accelerating growth on the quantity and nature of genetic variation, we present a new class of models capable of incorporating faster than exponential growth in a coalescent framework. Our work shows that such accelerated growth affects only the population size in the recent past and thus large samples are required to detect the models' effects on patterns of variation. When we compare models with fixed initial growth rate, models with accelerating growth achieve very large current population sizes and large samples from these populations contain more variation than samples from populations with constant growth. This increase is driven almost entirely by an increase in singleton variation. Moreover, linkage disequilibrium decays faster in populations with accelerating growth. When we instead condition on current population size, models with accelerating growth result in less overall variation and slower linkage disequilibrium decay compared to models with exponential growth. We also find that pairwise linkage disequilibrium of very rare variants contains information about growth rates in the recent past. Finally, we demonstrate that models of accelerating growth may substantially change estimates of present-day effective population sizes and growth times.
| S-EPMC3948808 | biostudies-other
Project description:Toll-like receptors (TLRs) are expressed not only in immune cells but also in a variety of tumor cells. Single-nucleotide polymorphisms (SNPs) located in the TLRs' promoter or the 3' untranslated region may affect gene expression by affecting the activity of the promoter or regulating the binding of mRNA to miRNA. This study aimed to investigate the association of the SNPs in TLR genes with the susceptibility to NSCLC. This case-control study involved 700 lung cancer patients and 700 healthy controls. All individuals were genotyped for all selected SNPs in TLR genes using polymerase chain reaction (PCR) test-based restriction fragment length polymorphism (PCR-RFLP) and TaqMan SNP genotyping assay. The association of genetic variations in TLRs with the susceptibility to NSCLC was evaluated by unconditional logistic regression with OR (95% CI). After evaluating transcriptional factor or miRNA binding capability by bioinformatics methods, six TLRs were identified for further analysis. We did not find that TLR3 rs5743303, TLR4 rs1927914, TLR4 rs11536891, TLR5 rs1640816, and TLR7 rs3853839 were associated with NSCLC risk (P > 0.05). Our data showed that TLR4 rs7869402?C?>?T polymorphism reduced the risk of NSCLC with OR (95% CI) of 0.63 (0.45-0.89). When stratified by gender and age, the individuals carrying at least one rs7869402T allele significantly decreased the NSCLC risk among males (OR?=?0.58, 95% CI?=?0.38-0.87) and among youngsters (OR?=?0.43, 95% CI?=?0.27-0.69). Smoking stratification analysis showed that the rs7869402T allele-containing genotype reduced the risk of NSCLC with OR (95% CI) of 0.50 (0.29-0.87) among smokers but not among nonsmokers (P > 0.05). When the individuals were classed by the pathological type, we found that the rs7869402T-containing genotype was associated with the risk of adenocarcinoma (OR?=?0.62, 95% CI?=?0.41-0.92) but not with that of squamous cell carcinoma (OR?=?0.71, 95% CI?=?0.44-1.13) and other types (OR?=?0.23, 95% CI?=?0.03-1.70). Compared with the TLR4 Ars1927914-Crs7869402-Trs11536891 haplotype, the Grs1927914-Trs7869402-Trs11536891 haplotype was associated with a decreased risk for developing NSCLC with OR (95% CI) of 0.57 (0.41-0.80). These results indicated that the TLR4 rs7869402 variation affects the genetic susceptibility to NSCLC.
| S-EPMC7171665 | biostudies-literature
Project description:OBJECTIVE:We previously reported that genetic variants in SORCS1 increase the risk of AD, that over-expression of SorCS1 reduces ?-secretase activity and A? levels, and that SorCS1 suppression increases ?-secretase processing of APP and A? levels. We now explored the effect of variation in SORCS1 on memory. METHODS:We explored associations between SORCS1-SNPs and memory retention in the NIA-LOAD case control dataset (162 cases,670 controls) and a cohort of Caribbean Hispanics (549 cases,544 controls) using single marker and haplotype analyses. RESULTS:Three SNPs in intron 1, were associated with memory retention in the NIA-LOAD dataset or the Caribbean Hispanic dataset (rs10884402(A allele:? = -0.15,p = 0.008), rs7078098(C allele:? = 0.18,p = 0.007) and rs950809(C allele:? = 0.17,p = 0.008)) and all three SNPs were significant in a meta-analysis of both datasets (0.002<p<0.03). The corresponding A-T-T haplotype for these SNPs was associated with lower scores in both datasets (p = 0.02,p = 0.0009), and the complementary G-C-C haplotype was associated with higher scores in NIA-LOAD (p = 0.02). These associations were restricted to cases. CONCLUSIONS:Variation in intron 1 in SORCS1 is associated with memory changes in AD.
| S-EPMC3202519 | biostudies-literature
Project description:The human immunodeficiency virus type 1 (HIV-1) promoter or long-terminal repeat (LTR) regulates viral gene expression by interacting with multiple viral and host factors. The viral transactivator protein Tat plays an important role in transcriptional activation of HIV-1 gene expression. Functional domains of Tat and its interaction with transactivation response element RNA and cellular transcription factors have been examined. Genetic variation within tat of different HIV-1 subtypes has been shown to affect the interaction of the viral transactivator with cellular and/or viral proteins, influencing the overall level of transcriptional activation as well as its action as a neurotoxic protein. Consequently, the genetic variability within tat may impact the molecular architecture of functional domains of the Tat protein that may impact HIV pathogenesis and disease. Tat as a therapeutic target for anti-HIV drugs has also been discussed.
| S-EPMC3414192 | biostudies-literature