ORCID Profile
0000-0002-4398-8237
Current Organisation
Vanderbilt University Medical Center
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Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2016
DOI: 10.1161/CIRCGENETICS.116.001572
Abstract: The burden of subclinical atherosclerosis in asymptomatic in iduals is heritable and associated with elevated risk of developing clinical coronary heart disease. We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent coronary heart disease. We studied a total of 25 109 European ancestry and African ancestry participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52 869 participants with common carotid intima–media thickness measured by ultrasonography within the CHARGE Consortium (Cohorts for Heart and Aging Research in Genomic Epidemiology). Participants were genotyped for 247 870 DNA sequence variants (231 539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and carotid intima–media thickness. APOB p.Arg3527Gln was associated with 4-fold excess CAC ( P =3×10 − 10 ). The APOE ε2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC ( P =1×10 − 12 ) and 1.4% reduced carotid intima–media thickness ( P =4×10 − 14 ) in carriers compared with noncarriers. In secondary analyses conditioning on low-density lipoprotein cholesterol concentration, the ε2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of ε2 was associated with reduced risk for coronary heart disease (odds ratio 0.77 P =1×10 − 11 ). Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE ε2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities, as well as clinical coronary heart disease.
Publisher: Wiley
Date: 16-02-2006
DOI: 10.1111/J.1464-5491.2005.01777.X
Abstract: Cardiovascular disease (CVD) is a major complication of Type 2 diabetes mellitus. The renin-angiotensin system (RAS) and nitric oxide production are both important regulators of vascular function and blood pressure. Genes encoding proteins involved in these pathways are candidates for a contribution to CVD in diabetic patients. We have investigated variants of the angiotensinogen (AGT), angiotensin converting enzyme (ACE), angiotensin type 1 receptor (AT1R) and endothelial nitric oxide synthase (NOS3) genes for association with subclinical measures of CVD in families with Type 2 diabetes mellitus (T2DM). Atherosclerosis was measured by carotid intima-media thickness and calcification of the carotid and coronary arteries in 620 European Americans and 117 African Americans in the Diabetes Heart Study. Because of the role of these systems in blood pressure regulation, blood pressure was also investigated. Compelling evidence of association was not detected with any of the SNPs with any outcome measures after adjustments for covariates despite sufficient power to detect relatively small differences in traits for specific genotype combinations. Genetic variation of the RAS and NOS3 genes do not appear to strongly influence subclinical cardiovascular disease or blood pressure in this diabetic population.
Publisher: Elsevier BV
Date: 03-2006
DOI: 10.1016/J.AHJ.2005.05.004
Abstract: CD40/CD40L signaling is known to play an important role in immune response. The proteins are expressed in a variety of cell types and ligation causes cells to produce inflammatory cytokines and cellular adhesion molecules. These processes are implicated in the development and progression of atherosclerosis. Animal models demonstrate that interruption of CD40/CD40L signaling produces a more fibrous and stable atherosclerotic lesion. We investigated the role of genetic variation in CD40 and CD40L genes in subclinical atherosclerosis assessed by coronary artery calcification (CAC) and carotid intima-media thickness in 620 in iduals from 230 families in the DHS. Two single nucleotide polymorphisms in the CD40 gene (rs1535045 and rs3765459) were significantly associated with decreased CAC (P < or = .02) in this population. CD40L single nucleotide polymorphisms were not significantly associated. In addition, no associations with carotid intima-media thickness, carotid artery calcification, or C-reactive protein levels were detected for either gene. Genetic variation in the CD40 gene is associated with CAC in diabetic families.
Publisher: The Endocrine Society
Date: 24-11-2020
Abstract: Glycogen storage diseases are rare. Increased glycogen in the liver results in increased attenuation. Investigate the association and function of a noncoding region associated with liver attenuation but not histologic nonalcoholic fatty liver disease. Genetics of Obesity-associated Liver Disease Consortium. Population-based. Computed tomography measured liver attenuation. Carriers of rs4841132-A (frequency 2%-19%) do not show increased hepatic steatosis they have increased liver attenuation indicative of increased glycogen deposition. rs4841132 falls in a noncoding RNA LOC157273 ~190 kb upstream of PPP1R3B. We demonstrate that rs4841132-A increases PPP1R3B through a cis genetic effect. Using CRISPR/Cas9 we engineered a 105-bp deletion including rs4841132-A in human hepatocarcinoma cells that increases PPP1R3B, decreases LOC157273, and increases glycogen perfectly mirroring the human disease. Overexpression of PPP1R3B or knockdown of LOC157273 increased glycogen but did not result in decreased LOC157273 or increased PPP1R3B, respectively, suggesting that the effects may not all occur via affecting RNA levels. Based on electronic health record (EHR) data, rs4841132-A associates with all components of the metabolic syndrome (MetS). However, rs4841132-A associated with decreased low-density lipoprotein (LDL) cholesterol and risk for myocardial infarction (MI). A metabolic signature for rs4841132-A includes increased glycine, lactate, triglycerides, and decreased acetoacetate and beta-hydroxybutyrate. These results show that rs4841132-A promotes a hepatic glycogen storage disease by increasing PPP1R3B and decreasing LOC157273. rs4841132-A promotes glycogen accumulation and development of MetS but lowers LDL cholesterol and risk for MI. These results suggest that elevated hepatic glycogen is one cause of MetS that does not invariably promote MI.
Publisher: Elsevier BV
Date: 04-2200
Publisher: Hindawi Limited
Date: 2010
DOI: 10.1155/2010/170153
Abstract: Aims . Genes of the 5-lipoxygenase pathway are compelling candidates for atherosclerosis. We hypothesize that polymorphisms in ALOX12, ALOX15, ALOX5 , and ALOX5AP genes are associated with subclinical atherosclerosis in multiple vascular beds. Methods . Families with two or more siblings with type 2 diabetes and their nondiabetic siblings were studied as part of the Diabetes Heart Study (DHS). European American diabetic ( n = 828 ) and nondiabetic ( n = 170 ) siblings were genotyped for SNPs in the ALOX12, ALOX15, ALOX5 , and ALOX5AP genes. Subclinical measures of atherosclerosis (IMT, coronary (CorCP), carotid (CarCP) and aortic (AorCP) calcified plaque) were obtained. Results . Associations were observed between ALOX12 with CorCP, ALOX5 with CorCP, AorCP, and IMT, and ALOX5AP with CorCP and CarCP, independent of known epidemiologic risk factors. Further, lipoxygenase pathway SNPs that were associated with measures of atherosclerosis were associated with markers of inflammation (CRP, ICAM-1) and calcification (MGP). Conclusions . Polymorphisms within ALOX12, ALOX5 , and ALOX5AP are genetically associated with subclinical atherosclerosis and with biomarkers of disease in families with type 2 diabetes. These results suggest that variants in lipoxygenase pathway genes may have pleiotropic effects on multiple components that determine risk of cardiovascular disease.
Publisher: Oxford University Press (OUP)
Date: 15-11-2007
DOI: 10.1093/AJE/KWM256
Abstract: Microvascular disease, reflected by retinal vascular changes, has been shown to predict clinical coronary heart disease. Whether retinal vascular changes are associated with subclinical coronary artery disease is unclear and was examined in this study. The authors conducted a multiethnic, population-based study of 6,147 persons aged 45-84 years, s led from six US communities in 2002-2004, who were free of clinical cardiovascular disease. Coronary artery calcification (CAC), a noninvasive measure of subclinical coronary artery disease, was assessed by cardiac computed tomography scanning and categorized into three groups of increasing severity: none (average CAC score = 0), mild (1-100), and moderate-to-severe (>100). Retinopathy signs and retinal vascular caliber were graded from retinal photographs following standardized protocols. After adjustment for age, gender, race/ethnicity, blood pressure, diabetes, lipid profile, smoking, and other risk factors, retinopathy was associated with having a moderate-to-severe CAC score (odds ratio = 1.43, 95% confidence interval: 1.18, 1.75). This association remained significant in both men and women and in persons with and without diabetes or hypertension. Variations in retinal vascular caliber were not significantly associated with CAC score. This study shows that retinopathy signs are independently associated with CAC, supporting the concept that common pathophysiologic processes may underlie both micro- and macrovascular disease.
Publisher: SAGE Publications
Date: 2008
Abstract: Epoxide hydrolase is involved in metabolism of vasoactive and anti-inflammatory epoxyeicosatrienoic acids to their corresponding diols. Consequently, epoxide hydrolase 2 ( EPHX2) is a candidate cardiovascular disease (CVD) gene. We investigated EPHX2 for association with subclinical CVD in European American (EA) and African American (AA) families from the Diabetes Heart Study. The R287Q polymorphism was associated with carotid artery calcified plaque (CarCP) in EAs. Other EPHX2 polymorphisms were associated with coronary artery calcified plaque (CorCP), CarCP or carotid artery intima-media thickness (IMT). Polymorphism rs7837347 was associated with all traits in the AAs (p=0.003, 0.001 and 0.017, respectively). Polymorphism rs7003694 displayed association with IMT (p=0.017) and, along with rs747276, a trend towards association with CorCP in diabetic EAs (p=0.057 and 0.080, respectively). These results provide additional evidence that EPHX2 contributes to the risk of subclinical CVD, although the true trait defining polymorphisms may not be identified and the effect size could be small.
Publisher: Public Library of Science (PLoS)
Date: 10-03-2011
Publisher: Oxford University Press (OUP)
Date: 11-2004
Publisher: Springer Science and Business Media LLC
Date: 15-07-2013
Publisher: American Diabetes Association
Date: 03-2006
DOI: 10.2337/DIABETES.55.03.06.DB05-0058
Abstract: In iduals with type 2 diabetes are at increased risk of cardiovascular disease (CVD) mortality and display increased levels of subclinical CVD. Genetic variation in PTPN1, a diabetes susceptibility gene, was investigated for a role in diabetic atherosclerosis. The PTPN1 gene encodes protein tyrosine phosphatase-1B, which is ubiquitously expressed and plays a role in the regulation of several signaling pathways. Subclinical atherosclerosis was assessed in 590 Caucasian participants with type 2 diabetes in the Diabetes Heart Study using B-mode ultrasound measurement of carotid intima-media thickness (IMT) and computed tomography measurement of carotid calcified plaque (CarCP) and coronary calcified plaque (CorCP). Twenty-three single nucleotide polymorphisms (SNPs) in PTPN1 were genotyped and assessed for association with IMT, CarCP, and CorCP. A total of 12 SNPs within a block of linkage disequilibrium encompassing the coding sequence of PTPN1 were significantly associated with CorCP (P values from & .0001 to 0.043) and 3 SNPs also within the block approached significance (P values from 0.058 to 0.066). In addition, a nine-SNP haplotype (GACTTCAGO) was also associated with increased CorCP under a dominant model (P = 0.01). No association was detected with IMT or CarCP. The associated SNPs and haplotype are the same as those observed to be associated with type 2 diabetes, insulin resistance, and fasting glucose in previous studies. With the inclusion of the most likely haplo-genotype for each in idual, the heritability estimate of CorCP increased from 0.53 ± 0.1 to 0.57 ± 0.1 (P = 8.1 × 10−10), suggesting a modest but detectable effect of this gene on the phenotype of CorCP in type 2 diabetic patients.
Publisher: Public Library of Science (PLoS)
Date: 10-05-2012
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-12-2022
Abstract: Persons with HIV have a higher prevalence of coronary artery disease compared with their HIV‐negative counterparts. Earlier identification of subclinical atherosclerosis may provide a greater opportunity for cardiovascular disease risk reduction. We investigated coronary cross‐sectional area (CorCSA) by noncontrasted computed tomography imaging as a noninvasive measure of arterial remodeling among virally suppressed persons with HIV. We assessed 105 persons with HIV with a spectrum of cardiometabolic health. All participants underwent computed tomography imaging to assess the mean corCSA of the proximal left anterior descending artery and 28 participants underwent additional coronary computed tomography angiography. Partial Spearman rank correlations adjusted for cardiovascular disease risk factors were used to assess relationships of corCSA with anthropometric measurements, HIV‐related factors, and plasma cytokines. Mean corCSA measured by noncontrast computed tomography and coronary computed tomography angiography were strongly correlated (ρ=0.91, P .0001). Higher mean corCSA was present in those with coronary artery calcium ( P =0.005) and it correlated with participants' atherosclerotic cardiovascular disease risk score (ρ=0.35, P =0.01). After adjusting for established cardiovascular disease risk factors, we observed an inverse relationship between corCSA and CD4 + T‐cell count (ρ=−0.2, P =0.047). Removal of age from the model strengthened the relationships between corCSA and antiretroviral therapy duration (from ρ=0.19, P =0.08 to ρ=0.3, P =0.01). CorCSA was also inversely correlated with plasma IL‐10 (ρ=−0.25, P =0.03) but had no relationship with IL‐6 (ρ=0.11, P =0.4) or IL‐1β (ρ=0.08, P =0.5). Positive coronary arterial remodeling, an imaging marker of subclinical atherosclerosis, is associated with a lower CD4 T‐cell count, lower circulating IL‐10, and possibly a longer antiretroviral therapy duration in persons with HIV. Clinicaltrials.gov Unique identifier: NCT04451980.
Publisher: The Endocrine Society
Date: 2007
DOI: 10.1210/JC.2006-0429
Abstract: Context: Cardiovascular disease is significantly increased in in iduals with type 2 diabetes mellitus (T2DM), especially in the presence of calcified atherosclerotic plaque. Fetuin A is an important mineralization inhibitor, and polymorphisms in the corresponding α2-Heremans-Schmid glycoprotein (AHSG) gene have been shown to be associated with serum fetuin A levels and free phosphate levels, as well as cardiovascular disease death. Objective: This study investigated whether polymorphisms in AHSG contribute to the development of calcified atherosclerotic plaque in the coronary and carotid arteries and to carotid artery intima-media thickness. Design: Eleven single nucleotide polymorphisms (SNPs) in AHSG were genotyped and evaluated for association with quantitative measures of subclinical atherosclerosis. Participants: Subjects were 829 T2DM-affected European Americans from 368 families in the Diabetes Heart Study. Main Outcome Measures: Participants were phenotyped for cardiovascular risk factors and atherosclerosis traits. The extent of coronary artery calcified plaque (CorCP) and carotid artery calcified plaque (CarCP) was measured using quantitative computed tomography, and carotid artery intima-media thickness was measured using high-resolution B mode ultrasonography. Results: Four SNPs in AHSG were nominally associated with CorCP in European Americans with T2DM (P & 0.05). Two 3-SNP haplotypes in the exon 6–7 region were associated with CorCP in European Americans with T2DM (P & 0.06). Conclusions: Sequence variants in the AHSG gene affect the extent of CorCP in T2DM-affected European Americans, consistent with the known biological role of AHSG in vascular calcification. These data implicate AHSG in the development of vascular calcified plaque in diabetic subjects.
Publisher: BMJ
Date: 09-2005
Publisher: Springer Science and Business Media LLC
Date: 09-2013
Publisher: Elsevier BV
Date: 2021
Publisher: Elsevier BV
Date: 06-2022
Location: United States of America
Location: United States of America
Location: United States of America
Location: United States of America
No related grants have been discovered for John Carr.