Abstract 14950: SLCO1B1 Genotype is Associated With Atorvastatin Discontinuation

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Deepak Voora ◽  
Jordan Baye ◽  
Adam D Mcdermaid ◽  
Smitha N Gowda ◽  
Larson A Eric ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Genetic Testing ◽  
Smoking Status ◽  
Clinical Care ◽  
Musculoskeletal Symptoms ◽  
Loss Of Function ◽  
Diagnosis Codes ◽  
Increased Risk ◽  
Patients At Risk ◽  
Concomitant Medications

Introduction: Atorvastatin is commonly prescribed to prevent cardiovascular disease; however, long-term adherence can be eroded by statin associated musculoskeletal symptoms (SAMS). Genetic variants in SLCO1B1 are associated with SAMS in patients using simvastatin; the association of these variants with adherence or SAMS has been less well characterized for atorvastatin. Methods: We tested the association between a loss of function genetic variant in SLCO1B1 and atorvastatin discontinuation in a large multi-specialty group practice. Using the electronic medical record (EMR) at Sanford Health, we defined a retrospective cohort of 8453 patients who were tested for SLCO1B1*5 (rs4149056, Val174Ala) through routine clinical care. Patients were included if they had received an atorvastatin prescription prior to genetic testing and had valid SLCO1B1 results. Patients were classified as discontinued (or not) based on their active medication list at the time of genetic testing. Clinical characteristics including demographics, diagnosis codes, smoking status, concomitant medications, and laboratory values for renal function and all creatine kinase (CK) values prior to testing, were extracted from the EMR. A Kruskal-Wallis test was used to compare longitudinal CK values vs. discontinuation. Logistic regression was used to test the relationship between SLCO1B1*5 and atorvastatin discontinuation for any reason. Results: There were 1752 patients available for analysis (mean age 64 years, 44% female, 2% non-Caucasian, 89% primary prevention indication). 1025 (58%) discontinued atorvastatin prior to SLCO1B1 testing. The number of SLCO1B1*5 alleles was associated with atorvastatin discontinuation (odds ratio per allele = 1.22, 95% confidence interval = 1.004 - 1.47, p = 0.04). Among the 495 patients with available CK levels, atorvastatin discontinuation was associated with higher mean CK levels than those who continued (Kruskal-Wallis test, p = 0.02). Conclusions: Atorvastatin discontinuation is common in real world patients at risk for cardiovascular disease. Carriers of SLCO1B1*5 are at increased risk for premature atorvastatin discontinuation - an effect which may reflect an excess risk of statin myopathy.

scholarly journals Genetics 101: understanding transmission and genetic testing of inherited bleeding disorders

2019 ◽  
Vol 6 (2) ◽  
pp. 10-17
Author(s):  
Eugenia Biguzzi ◽  
Karin van Galen ◽  
Rezan A Kadir
Keyword(s):  
Genetic Testing ◽  
Family History ◽  
Chorionic Villus ◽  
Bleeding Risk ◽  
Genetic Mutation ◽  
Severe Bleeding ◽  
Chorionic Villus Sampling ◽  
Bleeding Disorders ◽  
Loss Of Function ◽  
Increased Risk

Abstract Haemophilia is an X-linked inherited disorder that affects males and females, though the bleeding risk in girls and women has traditionally been under-recognised. About one third of haemophilia cases occur in individuals where there is no known family history. The gene mutations for rare bleeding disorders are not carried on the X chromosome and are therefore not sex-linked; however, the risk of passing on the condition is greatly increased for consanguineous parents where both parents may carry a copy of the fault in the genetic code which causes the condition. Genetic testing should be offered to every prospective mother, ideally before conception. This should be supported by counselling as the implications for family planning are profound. Von Willebrand factor (VWF) has an important role in primary and secondary haemostasis. Loss of function or low levels of VWF are associated with spontaneous bleeding causing nosebleeds, heavy periods and bruising as well as jpost-surgical bleeding. Joint bleeding and intracranial haemorrhage can also occur in those with a severe type of VWF. Diagnosis depends on bleeding assessment, family history and measurement of VWF. There are three types of VWD: Types 1 and 3 are caused by low or absent levels of VWD; Type 2 is caused by loss of function. Of these, Type 3 VWD is associated with the most severe bleeding risk but there is wide variation in bleeding phenotype among the other sub-types. The correlation between genetic mutation and bleeding phenotype is weak in VWD; therefore genetic testing is mainly useful for interpreting the risk when planning a family and to allow prenatal diagnosis in severe bleeding disorders. Genetic testing is essential for prospective parents to make fully informed decisions about having a family and how or whether to proceed with a pregnancy. The rationale for prenatal testing is to determine the bleeding status of the foetus and to inform decisions about managing delivery. Women may choose to terminate a pregnancy to avoid having a child with severe haemophilia. For some couples the option of adoption or not having children may be explored. Options for prenatal diagnostic testing include non-invasive methods, e.g. assessment of free foetal DNA in maternal plasma to determine the sex of a baby from 10 weeks in pregnancy, and invasive methods, e.g. chorionic villus sampling or amniocentesis, to determine the inheritance of the genetic mutation. Invasive methods are associated with a very small increased risk of pregnancy loss or early labour, which many couples feel is an unacceptable risk. Advanced techniques such as preimplantation screening also available, but require a huge commitment as this involves an IVF technique.

Abstract P369: Relation of Breast Arterial Calcification With Ankle Brachial Index

Circulation ◽  
2018 ◽  
Vol 137 (suppl_1) ◽  
Author(s):  
Carlos Iribarren ◽  
Tory Levine-Hall ◽  
Gabriela Sanchez ◽  
Bahman Sadeghi ◽  
Hanna Javan ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Smoking Status ◽  
Linear Regression Analysis ◽  
Ankle Brachial Index ◽  
Systolic Pressure ◽  
Care Program ◽  
Arterial Calcification ◽  
Cvd Risk ◽  
Cross Sectional ◽  
Increased Risk

Presence of breast arterial calcification (BAC) has been shown to be independently associated with increased risk of subclinical cardiovascular disease (CVD), angiographically-defined coronary disease and with incident coronary heart disease, stroke and heart failure. However, a relationship between BAC and peripheral vascular disease has not been established. The ankle brachial index (ABI) is an indicator of the severity of peripheral arterial disease (PAD) that predicts future CVD risk. We utilized cross-sectional data collected at the baseline examination (2012-15) of the MultIethNic Study of BrEast ARterial Calcium Gradation and CardioVAscular Disease (MINERVA Study), a cohort study of 5,145 post-menopausal women who were members of the Kaiser Permanente Medical Care Program of Northern California (KPNC) who were free of clinical CVD at baseline. Presence and gradation (in mg of calcium mass) of BAC in digital mammograms was ascertained with a validated densitometry method. ABI, the average of two ankle systolic pressure readings divided by the average of two brachial systolic pressure readings, was measured by trained and certified personnel after a ten-minute rest. A total of 3,693 women had complete data on all variables of interest; their mean (SD) age was 66 (4) years and 64% were white, 12% African-American, 14% Asian, 9% Latina and 1% mixed or other. While 28.2% presented with any detectable BAC (i.e., BAC mass > 0 mg), 5.4% had an ABI < 0.90. Three women had ABI>1.40 and were excluded from analyses (none had BAC>0). Prevalence of ABI < 0.90 was 4.8% (27/2,653) in women with BAC=0 and 6.9% (72/1,040) in women with any detectable BAC. The Odds Ratio of ABI<0.90 associated with any BAC was 1.39 (95% CI, 1.03-1.89) in a model adjusting for age and race/ethnicity, and was 1.38 (95% CI, 1.02-1.88) in a model with further adjustment for BMI, smoking status, diabetes, hypertension, LDL cholesterol, HDL cholesterol and hs-CRP. However, among women with any detectable BAC, standardized log_BAC mass (mg) was not significantly associated in bivariate linear regression analysis with ABI (slope=-0.0030 [SE=0.0031]; p=0.32). Our study demonstrates (for the first time) an independent association between presence of BAC and ABI indicative of PAD, with no apparent linear dose-response relationship.

scholarly journals Use of Pharmacogenetic Information in the Treatment of Cardiovascular Disease

2017 ◽  
Vol 63 (1) ◽  
pp. 177-185 ◽  
Author(s):  
Kevin Friede ◽  
Josephine Li ◽  
Deepak Voora
Keyword(s):  
Cardiovascular Disease ◽  
Clinical Practice ◽  
Genetic Variants ◽  
Drug Response ◽  
Clinical Care ◽  
Adverse Outcomes ◽  
Lipid Lowering ◽  
Successful Implementation ◽  
Average Dose ◽  
Increased Risk

Abstract BACKGROUND In 1964, Robert A. O'Reilly's research group identified members of a family who required remarkably high warfarin doses (up to 145 mg/day, 20 times the average dose) to achieve appropriate anticoagulation. Since this time, pharmacogenetics has become a mainstay of cardiovascular science, and genetic variants have been implicated in several fundamental classes of medications used in cardiovascular medicine. CONTENT In this review, we discuss genetic variants that affect drug response to 3 classes of cardiovascular drugs: statins, platelet P2Y12 inhibitors, and anticoagulants. These genetic variations have pharmacodynamic and pharmacokinetic effects and have been shown to explain differences in drug response such as lipid lowering, prevention of cardiovascular disease, and prevention of stroke, as well as incidence of adverse events such as musculoskeletal side effects and bleeding. Several groups have begun to implement pharmacogenetics testing as part of routine clinical care with the goal of improving health outcomes. Such strategies identify both patients at increased risk of adverse outcomes and alternative strategies to mitigate this risk as well as patients with “normal” genotypes, who, armed with this information, may have increased confidence and adherence to prescribed medications. While much is known about the genetic variants that underlie these effects, translation of this knowledge into clinical practice has been hampered by difficulty in implementing cost-effective, point-of-care tools to improve physician decision-making as well as a lack of data, as of yet, demonstrating the efficacy of using genetic information to improve health. SUMMARY Many genetic variants that affect individual responses to drugs used in cardiovascular disease prevention and treatment have been described. Further study of these variants is needed before successful implementation into clinical practice.

scholarly journals The Role of FER rs4957796 in the Risk of Developing and Dying from a Bloodstream Infection: A 23-Year Follow-up of the Population-based Nord-Trøndelag Health Study

2020 ◽  
Author(s):  
Tormod Rogne ◽  
Jan Kristian Damås ◽  
Helene Marie Flatby ◽  
Bjørn Olav Åsvold ◽  
Andrew Thomas DeWan ◽  
...  
Keyword(s):  
Bloodstream Infection ◽  
Case Fatality ◽  
Population Based ◽  
Health Study ◽  
Total Study Population ◽  
Diagnosis Codes ◽  
Increased Risk ◽  
Incidence And Mortality ◽  
Patients At Risk

Abstract Background Bloodstream infection and sepsis are major causes of health loss worldwide, and it is important to identify patients at risk of developing and dying from these conditions. The single-nucleotide polymorphism most strongly associated with sepsis mortality is FER rs4957796. However, it is not known how this variant is associated with bloodstream infection incidence and mortality. Methods We used prospective data from 1995–2017 from the population-based HUNT Study. Genotypes were ascertained from blood samples, and additional genotypes were imputed. Information on bloodstream infection and diagnosis codes at hospitalization were collected through record linkage with all hospitals in the area. Results A total of 69 294 patients were included. Patients with the rs4957796 CC genotype had an increased risk of developing a bloodstream infection compared with the TT genotype (hazard ratio [HR], 1.20; 95% confidence interval [CI], 1.00–1.43). However, there was a protective additive effect of the C allele in terms of mortality in the total study population (HR, 0.77; 95% CI, .64–.92 per copy of the C allele) and among bloodstream infection patients (odds ratio, 0.70; 95% CI, .58–.85 per copy of the C allele). The results did not appear to be affected by selection bias. Conclusions The rs4957796 CC genotype was associated with an increased risk of contracting a bloodstream infection but with a reduced risk of dying from one. The latter finding is in line with studies of sepsis case fatality, while the former expands our understanding of the immunoregulatory role of this polymorphism.

scholarly journals Loss-of-Function Mutations in Dnmt3a and Tet2 Lead to Accelerated Atherosclerosis and Convergent Macrophage Phenotypes in Mice

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 745-745 ◽  
Author(s):  
Philipp J. Rauch ◽  
Alexander J. Silver ◽  
Jk Gopakumar ◽  
Marie McConkey ◽  
Eti Sinha ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Bone Marrow ◽  
Rna Sequencing ◽  
De Novo ◽  
Lesion Size ◽  
Loss Of Function ◽  
Increased Risk ◽  
Donor Cells ◽  
Single Cell Rna Sequencing ◽  
Accelerate Atherosclerosis

Abstract Clonal hematopoiesis of indeterminate potential (CHIP) was recently identified as a major risk factor for development of both hematologic malignancies and atherosclerotic cardiovascular disease in humans. The most commonly mutated gene in CHIP, DNMT3A, is a de novo DNA methyltransferase. The second most commonly mutated gene is TET2, an enzyme which can lead to loss of DNA methylation, and thus is thought to have an opposing biochemical function to DNMT3A. Surprisingly, mutations in both genes lead to convergent phenotypes, such as clonal expansion of mutated stem cells, increased risk of malignant transformation, and increased risk of coronary heart disease. A molecular mechanism linking CHIP and cardiovascular disease has been explored only for loss of function mutations in the Tet2 gene (Jaiswal et al., NEJM 2017; Fuster et al., Science 2017). Here we tested the ability of null mutations in Dnmt3a to contribute to atherosclerosis in hypercholesteremic mice. We further explored the biological basis for this association through gene expression analyses and single-cell RNA sequencing. To model cardiovascular disease associated with DNMT3A-mutated CHIP, atherosclerosis-prone Ldlr-/- mice received bone marrow from Dnmt3a+/+ mice (WT), or from Dnmt3a-/- mice (KO) and WT mice in a 1:9 ratio to mimic a typical variant allele fraction observed in human CHIP. Mice then consumed a high-fat, high-cholesterol diet (HFD), and underwent assessment of atherosclerosis. At 9 weeks, mice that had received 10% Dnmt3a-/- bone marrow displayed an average lesion size that was 40% larger compared to mice receiving control marrow only (p=0.04). The increase in lesion size resembles that we previously observed in mice receiving Tet2-/- marrow (Jaiswal et al., NEJM 2017). De novo DNA methylation by Dnmt3a can alter gene expression. To elucidate how such changes may accelerate atherosclerosis, we first performed transcriptome analysis using bulk RNA sequencing of cholesterol-stimulated bone marrow derived macrophages (BMDM) from either WT or KO mice. BMDMs lacking Dnmt3a showed significantly augmented expression of genes belonging to the CXC chemokine cluster, Cxcl1, Cxcl2 and Cxcl3, as well as increases in mRNAs encoding canonical pro-inflammatory cytokines Il1b and Il6. These changes mirrored those we saw in macrophages lacking Tet2 (Jaiswal et al., NEJM 2017). We next asked how transcriptomic changes observed using the ex vivo BMDM system translated into the in vivo lesional environment. Single-cell RNA sequencing (10X Genomics) was performed on atherosclerotic aortae from mice that had been competitively transplanted with WT, Dnmt3a-/-, or Tet2-/- marrow at a 1:9 ratio. Clustering demonstrated broad changes in lesional immune cell composition in mice harboring CHIP. Lack of either Tet2 or Dnmt3a substantially expanded the myeloid compartment, containing cells that drive atherogenesis. A reciprocal reduction mainly affecting T lymphocyte populations accompanied this expansion. Within the myeloid cell compartment, Dnmt3a-/- or Tet2-/- donor cells, but not WT donor cells, gave rise to a distinct lesional macrophage population. These cells expressed markers associated with tissue-resident macrophages (Mrc1, Lyve1, F13a1), but also highly expressed several inflammatory mediators (Cxcl1, Pf4, Ccl2, Ccl7, Ccl8), and a characteristic set of transcription factors (Jun, Fos, Egr1). Overall, the present study reveals broad changes to the lesional cellular composition and transcriptome induced by the most common CHIP mutations, and provides novel insight into the mechanisms by which CHIP accelerates atherosclerosis. Despite exerting opposite catalytic functions, lack of Dnmt3a or of Tet2 function lead to a myriad of similar downstream transcriptomic and cellular changes. These results indicate that mutations in Dnmt3a and Tet2 accelerate atherosclerosis through convergent mechanisms. Disclosures No relevant conflicts of interest to declare.

Lifestyle-Related Risk Factors, Smoking Status and Cardiovascular Disease

2012 ◽  
Vol 19 (2) ◽  
pp. 85-92
Author(s):  
Renata Giudice ◽  
Raffaele Izzo ◽  
Maria Virgina Manzi ◽  
Giampiero Pagnano ◽  
Mario Santoro ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cardiovascular Disease ◽  
Smoking Status ◽  
Related Risk

Circulating Stem/Progenitor Cells as Prognostic Biomarkers in Macro- and Microvascular Disease: A Narrative Review of Prospective Observational Studies

2018 ◽  
Vol 25 (35) ◽  
pp. 4507-4517 ◽  
Author(s):  
Mauro Rigato ◽  
Gian Paolo Fadini
Keyword(s):  
Cardiovascular Disease ◽  
Progenitor Cells ◽  
Cardiovascular Events ◽  
Observational Studies ◽  
English Language ◽  
Microvascular Disease ◽  
Patient Characteristics ◽  
Diabetic Patients ◽  
Increased Risk ◽  
Cell Phenotypes

Background: Circulating progenitor cells (CPCs) and endothelial progenitor cells (EPCs) are immature cells involved in vascular repair and related to many aspects of macro and microvascular disease. <p> Objective: We aimed to review studies reporting the prognostic role of CPCs/EPCs measurement on development of cardiovascular disease and microangiopathy. <p> Methods and Results: We reviewed the English language literature for prospective observational studies reporting the future development of cardiovascular disease or microangiopathy in patients having a baseline determination of CPCs/EPCs. We retrieved 34 studied reporting on cardiovascular outcomes and 2 studies reporting on microvascular outcomes. Overall, a reduced baseline level of CPCs/EPCs was associated with a significant increased risk of cardiovascular events, all-cause death, and onset/progression of microangiopathy. The most predictive phenotypes were CD34+ and CD34+CD133+. The main limitation was related to the high heterogeneity among studies in terms of patient characteristics and cell phenotypes. <p> Conclusion: The present review shows that a reduced level of circulating progenitor cells is a risk factor for the development of future cardiovascular events and death. In addition, low CPCs/EPCs levels predict the onset or worsening of microalbuminuria and retinopathy in diabetic patients.

Subclinical Thyroid Dysfunction and the Risk of Cardiovascular Disease

2020 ◽  
Vol 26 (43) ◽  
pp. 5617-5627
Author(s):  
Mirjana Stojković ◽  
Miloš Žarković
Keyword(s):  
Cardiovascular Disease ◽  
Risk Factor ◽  
Cardiac Electrophysiology ◽  
Vascular System ◽  
Density Lipoprotein ◽  
Thyroid Stimulating Hormone ◽  
Normal Limits ◽  
Developing Heart ◽  
Treatment Indications ◽  
Increased Risk

The prevalence of subclinical hypothyroidism (SH) is 3-10%. The prevalence of subclinical hyperthyroidism (SHr) is 0.7-9.7%. Thyroid hormones affect cardiac electrophysiology, contractility, and vasculature. SH is associated with an increased risk of coronary heart disease (CHD), especially in subjects under 65. SHr seems to be associated with a slightly increased risk of CHD and an increase in CHD-related mortality. Both SH and SHr carry an increased risk of developing heart failure (HF), especially in those under 65. Both SH and SHr are associated with worse prognoses in patients with existing HF. SH is probably not associated with atrial fibrillation (AF). SHr, low normal thyroid-stimulating hormone (TSH) and high normal free thyroxine (FT4) are all associated with the increased risk of AF. An association between endothelial dysfunction and SH seems to exist. Data regarding the influence of SHr on the peripheral vascular system are conflicting. SH is a risk factor for stroke in subjects under 65. SHr does not increase the risk of stroke. Both SH and SHr have an unfavourable effect on cardiovascular disease (CVD) and all-cause mortality. There is a U-shaped curve of mortality in relation to TSH concentrations. A major factor that modifies the relation between subclinical thyroid disease (SCTD) and mortality is age. SH increases blood pressure (BP). SHr has no significant effect on BP. Lipids are increased in patients with SH. In SHr, high-density lipoprotein cholesterol and lipoprotein( a) are increased. SCTD should be treated when TSH is over 10 mU/l or under 0.1 mU/l. Treatment indications are less clear when TSH is between normal limits and 0.1 or 10 mU/L. The current state of knowledge supports the understanding of SCTD’s role as a risk factor for CVD development. Age is a significant confounding factor, probably due to age-associated changes in the TSH reference levels.

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