Genetics of atherosclerosis: Some strategies for studies of apolipoprotein E

Many genes are hypothesized to be involved in determining an individual's risk for coronary artery disease (CAD). Recent efforts have focused on the genetic architecture of quantitative traits related to risk for CAD. Studies relating genetic variation in the structural gene for apolipoprotein E to plasma levels of apolipoprotein E illustrate strategies to begin to understand the genetic architecture of plasma levels of apolipoprotein E. Studies using a measured gene approach suggest that variability in the isoforms of apolipoprotein E explain some, but not all, of the variability in plasma levels of apolipoprotein E. Products of other genes may be associated with plasma apolipoprotein E variability. No studies to date have presented findings from an unmeasured gene approach to plasma levels of apolipoprotein E. Models most often used in the unmeasured gene approach are not appropriate for studies of plasma levels of apolipoprotein E and perhaps are inappropriate for the study of other traits. Variations of the models are suggested to ask if a single unmeasured gene is the same gene defined by the apolipoprotein E isoforms. Another model can be used to ask if there is evidence for genes influencing levels of apolipoprotein E after accounting for the effects of the isoforms. Both the measured gene and unmeasured gene strategies have limitations. The failure of most models to allow for the complexity of genotype-phenotype relationships or the heterogeneity of genetic causes will slow the progress to understand the genetic architecture of quantitative traits associated with risk for CAD. © 1993 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38555/1/1310050409_ftp.pd

Genetic Research and Women’s Heart Disease: a Primer

PURPOSE OF REVIEW: This review provides a brief synopsis of sexual dimorphism in atherosclerosis with an emphasis on genetic studies aimed to better understand the atherosclerotic process and clinical outcomes in women. Such studies are warranted because development of atherosclerosis, impact of several traditional risk factors, and burden of coronary heart disease (CHD) differ between women and men. RECENT FINDINGS: While most candidate gene studies pool women and men and adjust for sex, some sex-specific studies provide evidence of association between candidate genes and prevalent and incident CHD in women. So far, most genome-wide association studies (GWAS) also failed to consider sex-specific associations. The few GWAS focused on women tended to have small sample sizes and insufficient power to reject the null hypothesis of no association even if associations exist. SUMMARY: Few studies consider that sex can modify the effect of gene variants on CHD. Sufficiently large-scale genetic studies in women of different race/ethnic groups, taking into account possible gene-gene and gene-environment interactions as well as hormone-mediated epigenetic mechanisms, are needed. Using the same disease definition for women and men might not be appropriate. Accurate phenotyping and inclusion of relevant outcomes in women, together with targeting the entire spectrum of atherosclerosis, could help address the contribution of genes to sexual dimorphism in atherosclerosis. Discovered genetic loci should be taken forward for replication and functional studies to elucidate the plausible underlying biological mechanisms. A better understanding of the etiology of atherosclerosis in women would facilitate future prevention efforts and interventions

Quantification of coronary artery calcium by electron beam computed tomography for determination of severity of angiographic coronary artery disease in younger patients

Objectives.This study attempted to 1) evaluate five quantitative measures of coronary artery calcium and determine which best agreed with coronary artery disease severity at angiography; and 2) determine optimal quantity cutpoints to distinguish among no, mild and significant disease.Background.Coronary artery calcium identified noninvasively by electron beam computed tomography is a sensitive marker for atherosclerosis. Quantitative assessments of calcium could distinguish among patients with no, mild and significant disease in clinical, screening and research settings.Methods.One hundred sixty patients, 23 to 59 years old, underwent coronary angiography and electron beam computed tomography. Coronary artery calciumwas defined as dense (> 130 Hounsfield units) foci ≥2 mm2on the tomogram. Regression and receiver operating characteristic analyses were used to evaluate five quantitative measures of calcium as predictors of the largest stenosis in the coronary arteries and to identify optimal cutpoints for distinguishing among disease categories. No diseasewas defined as no stenosis, mild diseaseas 10% to 49% diameter stenosis in one or more major branches and significant diseaseas ≥ 50% diameter stenosis in one or more major branches.Results.All measures evaluated performed well. With calcific area as the quantitative measure, the best cutpoint for discriminating between patients with and without disease was the presence of calcium: sensitivity 81%, specificity 86% and overall accuracy 83%. The best cutpoint for discriminating between patients with and without significant disease was 18 mm2: sensitivity 86%, specificity 81% and accuracy 83%.Conclusions.Because the ranges of calcium quantity overlapped across disease categories, no cutpoints would distinguish among categories with absolute certainty. However, selected cutpoints could rule out disease in most healthy subjects and identify most patients with significant disease

A path analysis of the causal relationships between red cell glycolytic intermediates, ADP and ATP in sickle cell anemia

The statistical relationships among the glycolytic intermediates (GIs) of the Embden-Meyerhof pathway, adenine nucleotides (ANs) and various hematological measures were estimated for 34 sickle cell anemia patients. Heterogeneity in linear and quadratic regressions of hemoglobin and hematocrit, both singly and jointly, on the GI and AN variables implied 1) that any single formula to standardize optical density measures of the GIs and ANs on a per gram hemoglobin or per liter cell water basis would not uniformly remove hemoglobin and hematocrit effects; 2) that ignoring significant hematological effects could bias the estimates of correlation among GIs and ANs; and 3) that hemoglobin and hematocrit measures do not reflect the same source of variability.The correlations among the GIs and ANs, after adjustment for hematological variability, were analyzed by path analysis to determine which of five proposed path models for cause and effect relationships were compatible with the data. AMP had a greater influence on ADP (coefficient of determination (CD) = 23%) than all the GIs together, while G6P and ADP influenced ATP variability the most (CD = 33% and 12%). The contributions of unknown factors to ADP and ATP variability were large for all models (CD = 56-77%) possibly due to stress of sickle cell disease. The path model with AMP and the four GIs (G6P, F6P, FDP, DHAP) influencing ADP variation, and the same GIs and ADP influencing ATP was the model most compatible with the data.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/22789/1/0000345.pd

The cis and trans effects of the risk variants of coronary artery disease in the Chr9p21 region

Abstract Background Recent genome-wide association studies (GWAS) have shown that single nucleotide polymorphisms (SNPs) in the Chr9p21 region are associated with coronary artery disease (CAD). Most of the SNPs identified in this region are non-coding SNPs, suggesting that they may influence gene expression by cis or trans mechanisms to affect disease susceptibility. Since all cells from an individual have the same DNA sequence variations, levels of gene expression in immortalized cell lines can reflect the functional effects of DNA sequence variations that influence or regulate gene expression. The objective of this study is to evaluate the functional consequences of the risk variants in the Chr9p21 region on gene expression. Methods We examined the association between the variants in the Chr9p21 region and the transcript-level mRNA expression of the adjacent genes (cis) as well as all other genes across the whole genome (trans) from transformed beta-lymphocytes in 801 non-Hispanic white participants from The Genetic Epidemiology Network of Arteriopathy (GENOA) study. Results We found that the CAD risk variants in the Chr9p21 region were significantly associated with the mRNA expression of the ANRIL transcript ENST00000428597 (p = 8.58e-06). Importantly, a few distant transcripts were also found to be associated with the variants in this region, including the well-known CAD risk gene ABCA1 (p = 1.01e-05). Gene enrichment testing suggests that retinol metabolism, N-Glycan biosynthesis, and TGF signaling pathways may be involved. Conclusion These results suggest that the effect of risk variants in the Chr9p21 region on susceptibility to CAD is likely to be mediated through both cis and trans mechanisms.http://deepblue.lib.umich.edu/bitstream/2027.42/111638/1/12920_2015_Article_94.pd

Hypertension during Pregnancy is Associated with Coronary Artery Calcium Independent of Renal Function

Abstract Background: Hypertension during pregnancy (HDP) increases the risk of future coronary heart disease (CHD), but it is unknown whether this association is mediated by renal injury. Reduced renal function is both a complication of HDP and a risk factor for CHD. Methods: Logistic regression models were fit to examine the association between a history of HDP and the presence and extent of coronary artery calcification (CAC), a measure of subclinical coronary artery atherosclerosis, in 498 women from the Epidemiology of Coronary Artery Calcification Study (mean age 63.3+/-9.3 years). Results: Fifty-two (10.4%) women reported a history of HDP. After adjusting for age at time of study participation, HDP was associated with increased serum creatinine later in life (p=0.014). HDP was positively associated with the presence of CAC after adjusting for age at time of study participation (OR=2.7, 95% CI 1.4-5.4). This association was slightly attenuated with adjustment for body size and blood pressure (OR=2.4, 95% CI 1.2-4.9) but was not further attenuated with adjustment for serum creatinine and urinary albumin/creatinine ratio (OR=2.6, 95% CI 1.3-5.3). Results were similar for CAC extent. Conclusions: HDP may increase a woman's risk of future CHD beyond traditional risk factors and renal function. Women with a history of HDP should be monitored for potential increased risk of CHD as they age.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78144/1/jwh.2008.1285.pd

Circulating CD34+ Cell Count is Associated with Extent of Subclinical Atherosclerosis in Asymptomatic Amish Men, Independent of 10-Year Framingham Risk

Background Bone-marrow derived progenitor cells (PCs) may play a role in maintaining vascular health by actively repairing damaged endothelium. The purpose of this study in asymptomatic Old Order Amish men (n = 90) without hypertension or diabetes was to determine if PC count, as determined by CD34+ cell count in peripheral blood, was associated with 10-year risk of cardiovascular disease (CVD) and measures of subclinical atherosclerosis. Methods and Results CD34+ cell count by fluorescence-activated cell sorting, coronary artery calcification (CAC) by electron beam computed tomography, and CVD risk factors were obtained. Carotid intimal-medial thickness (CIMT) also was obtained in a subset of 57 men. After adjusting for 10-year CVD risk, CD34+ cell count was significantly associated with CAC quantity ( p =0.03) and CIMT ( p < 0.0001). A 1-unit increase in natural-log transformed CD34+ cell count was associated with an estimated 55.2% decrease (95% CI: −77.8% to −9.3%) in CAC quantity and an estimated 14.3% decrease (95% CI: −20.1% to −8.1%) in CIMT. Conclusions Increased CD34+ cell count was associated with a decrease in extent of subclinical atherosclerosis in multiple arterial beds, independent of 10-year CVD risk. Further investigations of associations of CD34+ cell count with subclinical atherosclerosis in asymptomatic individuals could provide mechanistic insights into the atherosclerotic process

Histopathology of familial versus nonfamilial dilated cardiomyopathy

Idiopathic dilated cardiomyopathy is most likely a heterogenous group of diseases characterized by ventricular dilatation and dysfunction. Approximately 20% of patients with idiopathic dilated cardiomyopathy have familial disease, which may be inapparent by review of the family history alone. It has been suggested that histopathologic features, particularly the presence of bizarrely shaped mitochondria, may be useful in distinguishing familial from nonfamilial disease.We investigated 57 patients with dilated cardiomyopathy, 13 familial and 43nonfamilial or indeterminate. Pathologic examination of right endomyocardial biopsy specimens showed no significant differences between the familial, nonfamilial, or indeterminate groups by light microscopy or electron microscopy. We conclude that the distinction between familial and nonfamilial dilated cardiomyopathy cannot be made by histopathologic examination in most cases.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30544/1/0000177.pd