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Ciccarone Articles

Ciccarone Center Research

Topic

Genetics

Landmark Article

Association of single nucleotide polymorphisms on chromosome 9p21.3 with platelet reactivity: a potential mechanism for increased vascular disease.
By: Musunuru K, Post WS, Herzog W, Shen H, O’Connell JR, McArdle PF, Ryan KA, Gibson Q, Cheng YC, Clearfield E, Johnson AD, Tofler G, Yang Q, O’Donnell CJ, Becker DM, Yanek LR, Becker LC, Faraday N, Bielak LF, Peyser PA, Shuldiner AR, Mitchell BD.
Genome-wide association studies have identified a locus on chromosome 9p21.3 to be strongly associated with myocardial infarction/coronary artery disease and ischemic stroke. To gain insights into the mechanisms underlying these associations, we hypothesized that SNPs in this region would be associated with platelet reactivity across multiple populations. Subjects in the initial population included 1,402 asymptomatic Amish adults in whom we measured platelet reactivity and CAC. Our results suggest that risk alleles at 9p21.3 locus may have pleiotropic effects on myocardial infarction/coronary artery disease and stroke risk, possibly through their influence on platelet reactivity.
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Association of SNPs on chromosome 9p21.3 with platelet reactivity: A potential mechanism for increased vascular disease.
By: Musunuru K, Post WS, Herzog W, Shen H, O’Connell JR , Peyser PA, Faraday N, Shuldiner AR, Mitchell BD.

Genome-wide association studies have identified a locus on chromosome 9p21.3 to be strongly associated with myocardial infarction/coronary artery disease and ischemic stroke. To gain insights into the mechanisms underlying these associations, we hypothesized that single nucleotide polymorphisms (SNPs) in this region would be associated with platelet reactivity across multiple populations. Results suggest that risk alleles at 9p21.3 locus may have pleiotropic effects on myocardial infarction/coronary artery disease and stroke risk, possibly through their influence on platelet reactivity.

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Associations of SNPs in ADIPOQ and subclinical cardiovascular disease in MESA.
By: Wassel CL, Pankow JS, Rassmussen-Torvik LJ, Li N, Taylor KD, Guo X, Palmas WR, Post WS.

Circulating adiponectin is associated with both clinical and subclinical cardiovascular disease (CVD). Variants of the adiponectin gene (ADIPOQ) are associated with clinical CVD, but little is known about associations with subclinical CVD. We studied the association of 11 ADIPOQ single-nucleotide polymorphisms (SNPs) with common and internal carotid intima media thickness (cIMT), presence of coronary artery calcification (CAC), and CAC scores (in those with CAC) in 2,847 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). Participants were white (n = 712), African American (n = 712), Chinese (n = 718), and Hispanic (n = 705). All models were adjusted for age, sex, and field site, and stratified by race/ethnic group. African Americans with genotypes AG/GG of rs2241767 had 36% greater (95% confidence interval (CI; 16%, 59%), P = 0.0001) CAC prevalence; they also had a larger common cIMT (P = 0.0043). Also in African Americans, genotypes AG/AA of rs1063537 were associated with a 35% (95% CI (14%, 59%), P = 0.0005) greater CAC prevalence. Hispanics with the AA genotype of rs11711353 had a 37% (95% CI (14%, 66%), P = 0.0011), greater CAC prevalence compared to those with the GG genotype. Additional adjustment for ancestry in African-American and Hispanic participants did not change the results. No single SNP was associated with subclinical CVD phenotypes in Chinese or white participants. There appears to be an association between ADIPOQ SNPs and subclinical CVD in African Americans and Hispanics. Replication as well as assessment of other ADIPOQ SNPs is warranted.

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Associations between genetic variants in the ACE, AGT, AGTR1 and AGTR2 genes and renal function in the multi-ethnic study of atherosclerosis.
By: Campbell CY, Fang BF, Guo X, Peralta CA, Psaty BM, Rich SS, Young JH, Coresh J, Kramer HJ, Rotter JI, Post WS.

These data suggest that genetic polymorphisms in the renin-angiotensin system are associated with renal phenotypes in the general population, but that many associations differ across racial/ethnic groups.

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Identifying patients at high risk of a cardiovascular event in the near future: current status and future directions: report of a national heart, lung, and blood institute working group.
By: Eagle KA, Ginsburg GS, Musunuru K, Aird WC, Balaban RS, Bennett SK, Blumenthal RS, Coughlin SR, Davidson KW, Frohlich ED, Greenland P, Jarvik GP, Libby P, Pepine CJ, Ruskin JN, Stillman AE, Van Eyk JE, Tolunay HE, McDonald CL, Smith SC Jr.
The National Heart, Lung, and Blood Institute convened a working group to provide basic and clinical research recommendations on the development of an integrated approach for identifying those individuals who are at high risk for a cardiovascular event, such as acute coronary syndromes (ACS) or sudden cardiac death in the “near term.” The participants reviewed current clinical cardiology practices for risk assessment and state-of-the-science techniques in several areas, including biomarkers, proteomics, genetics, psychosocial factors, imaging, coagulation, and vascular and myocardial susceptibility. This report presents highlights of these reviews and a summary of suggested research directions.
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Genome-wide association study identifies GPC5 as a novel genetic locus protective against sudden cardiac arrest.
By: Arking DE, Reinier K, Post W, Jui J, Hilton G, O’Connor A, Prineas RJ, Boerwinkle E, Psaty BM, Tomaselli GF, Rea T, Sotoodehnia N, Siscovick DS, Burke GL, Marban E, Spooner PM, Chakravarti A, Chugh SS.
A novel genetic locus for sudden cardiac arrest (SCA), GPC5, was identified from Oregon-Sudden Unexpected Death Study (SUDS) and successfully validated in the ARIC and CHS cohorts. Three other members of the Glypican family have been previously implicated in human disease, including cardiac conditions. The mechanism of this specific association requires further study.
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NOS1AP variant associated with incidence of type 2 diabetes in calcium channel blocker users in the Atherosclerosis Risk in Communities (ARIC) study.
By: Chu AY, Coresh J, Arking DE, Pankow JS, Tomaselli GF, Chakravarti A, Post WS, Spooner PH, Boerwinkle E, Kao WH.

We have independently replicated the association between rs10494366 in NOS1AP (the gene encoding nitric oxide synthase-1 adaptor protein) and incident diabetes among white calcium channel blocker users. Further exploration of NOS1AP variants and type 2 diabetes and functional studies of NOS1AP in type 2 diabetes pathology is warrranted.

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Association of scavenger receptor class B type I polymorphisms with subclinical atherosclerosis: the Multi-Ethnic Study of Atherosclerosis.
By: Naj AC, West M, Rich SS, Post W, Kao WH, Wasserman BA, Herrington DM, Rodriguez A.
Little is known about the association of scavenger receptor class B type I (SCARB1) single-nucleotide polymorphisms (SNPs) and subclinical atherosclerosis, particularly in subjects of different racial/ethnic backgrounds. We examined this relationship in the Multi-Ethnic Study of Atherosclerosis and found that variation in SCARB1 at rs10846744 was significantly associated with common carotid intimal-medial artery thickness across racial/ethnic groups.
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Integrative predictive model of coronary artery calcification in atherosclerosis.
By: McGeachie M, Ramoni RL, Mychaleckyj JC, Furie KL, Dreyfuss JM, Liu Y, Herrington D, Guo X, Lima JA, Post W, Rotter JI, Rich S, Sale M, Ramoni MF.
Many different genetic and clinical factors have been identified as causes or contributors to atherosclerosis. We present a model of preclinical atherosclerosis based on genetic and clinical data that predicts the presence of coronary artery calcification in healthy Americans of European descent 45 to 84 years of age in the MESA study. Our investigation of joint genetic and clinical factors associated with atherosclerosis shows predictive results for both cases, as well as enhanced performance for their combination.
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