Search PubMed⌕ Search

Biomedical subjects

Sekar Kathiresan

Publications and source records attributed to Sekar Kathiresan.

At least 19 recordsLinked to original sources
PubMed2006

New opportunities for identification and reduction of coronary risk: treatment of vulnerable patients, arteries, and plaques.

Advances in the understanding of the role of vulnerable plaque in the causation of coronary events, coupled with novel diagnostic and therapeutic approaches, create a new opportunity for progress against cardiovascular disease. The recognition that non-flow-limiting plaques often produce cardiac events has led to the development of invasive and non-invasive methods to identify such plaques prospectively. Treatments such as stenting, photodynamic therapy, and novel pharmaceutical agents are under consideration as methods to stabilize the vulnerable plaques and patients that might be detected, thereby enhancing both primary and secondary prevention. Despite the promise of the field, many issues remain to be resolved, including the focality versus systemic nature of the atherosclerotic process, the ability of detectors to identify the target for which they were developed and prove that such a target is linked to clinical events, and the efficacy of specific therapy. If vulnerable plaques and patients can be successfully identified and treated, there will be immense clinical benefits, accompanied by cost savings.

Coronary Artery Disease↗
PubMed2006

Common genetic variation in five thrombosis genes and relations to plasma hemostatic protein level and cardiovascular disease risk.

OBJECTIVE: We undertook a linkage disequilibrium (LD)-based genetic approach to investigate the hypothesis that common sequence variants in 5 thrombosis genes influence plasma hemostatic protein levels or risk of cardiovascular disease (CVD). METHODS AND RESULTS: In a reference panel, we characterized LD structure at the fibrinogen gene cluster (fibrinogen-beta[FGB], FGA, and FGG), factor VII (F7), and tissue plasminogen activator (PLAT) loci. Forty-one tag single nucleotide polymorphisms (SNPs) were genotyped in 1811 unrelated Framingham Heart Study participants. There were significant associations of 9 FGB SNPs with fibrinogen level (minimum P=0.002) and of 7 F7 SNPs and factor VII level (minimum P<0.0001). SNPs at the PLAT locus were not associated with PLAT level. In stepwise analysis, a single FGB variant explained 1% of the residual variance in fibrinogen level, and 2 F7 SNPs together explained 10% of the residual variance in factor VII level. Two PLAT haplotypes were associated with CVD (multivariable-adjusted global P=0.0004). CONCLUSIONS: A comprehensive survey of common sequence variation demonstrates that cis-regulatory SNPs explain a modest proportion of the residual variance in circulating fibrinogen and factor VII level and PLAT haplotypes increase the risk of CVD. Additional studies are warranted to confirm the association of PLAT sequence variation and risk of CVD.

Aged↗
PubMed2006

Contribution of clinical correlates and 13 C-reactive protein gene polymorphisms to interindividual variability in serum C-reactive protein level.

BACKGROUND: Serum C-reactive protein (CRP) level is a heritable complex trait that predicts incident cardiovascular disease. We investigated the clinical and genetic sources of interindividual variability in serum CRP. METHODS AND RESULTS: We studied serum CRP in 3301 Framingham Heart Study (FHS) participants (mean age 61 years, 53% women). Twelve clinical covariates explained 26% of the variability in CRP level, with body mass index alone explaining 15% (P<0.0001) of the variance. To investigate the influence of genetic variation at the CRP gene on CRP levels, we first constructed a dense linkage disequilibrium map for common single-nucleotide polymorphisms (SNPs) spanning the CRP locus (1 SNP every 850 bases, 26 kilobase [kb] genomic region). Thirteen CRP SNPs were genotyped in 1640 unrelated FHS participants with measured CRP levels. After adjustment for clinical covariates, 9 of 13 SNPs were associated with CRP level (P<0.05). To account for correlation among SNPs, we conducted forward stepwise selection among all 13 SNPs; a triallelic SNP (rs3091244) remained associated with CRP level (stepwise P<0.0001). The triallelic SNP (C-->T-->A; allele frequencies 62%, 31%, and 7%), located in the promoter sequence, explained 1.4% of total serum CRP variation; haplotypes harboring the minor T and A alleles of this SNP were associated with higher CRP level (haplotype P=0.0002 and 0.004). CONCLUSIONS: In our community-based sample, clinical variables explained 26% of the interindividual variation in CRP, whereas a common triallelic CRP SNP contributed modestly. Studies of larger samples are warranted to assess the association of genetic variation in CRP and risk of cardiovascular disease.

Age Factors↗
PubMed2006

Cross-sectional relations of multiple biomarkers from distinct biological pathways to brachial artery endothelial function.

BACKGROUND: Endothelial dysfunction is a critical intermediate phenotype in the pathogenesis of cardiovascular disease. We evaluated the relative contributions of distinct biological pathways to interindividual variation in endothelial function by relating prototype biomarkers (representing these pathways) to brachial artery vasodilator function. METHODS AND RESULTS: We investigated the cross-sectional relations of a panel of 7 biomarkers measured at a routine examination to brachial artery vasodilator function (flow-mediated dilation [FMD] and reactive hyperemia) assessed at a subsequent examination (mean interval, 2.9 years) in 2113 Framingham Heart Study participants (mean age, 61 years; 54% women). We selected biomarkers from 4 biological domains: neurohormonal (N-terminal pro-atrial natriuretic peptide [N-ANP], B-type natriuretic peptide [BNP], renin, aldosterone), hemostatic factors (plasminogen activator inhibitor-1 [PAI-1]), inflammation (C-reactive protein [CRP]), and target organ damage (urine albumin-creatinine ratio). In age- and sex-adjusted models, several biomarkers were related to baseline brachial artery diameter (PAI-1, CRP, urine albumin-creatinine ratio), baseline mean flow (N-ANP, BNP, PAI-1, CRP, aldosterone), FMD (N-ANP, PAI-1, CRP, renin), and reactive hyperemia (BNP, PAI-1, CRP, renin, urine albumin-creatinine ratio). In multivariable analyses relating the 7 biomarkers conjointly to each vascular function measure (adjusting for known risk factors), N-ANP and renin were positively related to FMD (P=0.001 and P=0.04, respectively), and N-ANP was inversely related to baseline mean flow velocity (P=0.01). None of the other biomarkers was significantly related to the vascular function measures studied. CONCLUSIONS: In our large community-based sample, a conservative strategy relating several biomarkers to vascular endothelial function identified plasma N-ANP as a key correlate of mean flow under basal conditions and of FMD in response to forearm cuff occlusion.

Aged↗
PubMed2006

PAI-1 Gene 4G/5G polymorphism and risk of type 2 diabetes in a population-based sample.

Elevated plasma levels of plasminogen activator inhibitor-1 (PAI-1) increase risk for type 2 diabetes. The PAI-1 4G/5G polymorphism is a major genetic determinant of plasma PAI-1 levels, with 4G/4G homozygotes having elevated PAI-1 levels relative to 5G allele carriers. These observations suggest the hypothesis that the PAI-1 4G/5G polymorphism could be a genetic risk factor for diabetes. We tested this hypothesis among 2169 participants of the Framingham Offspring Study followed for seven examinations over 26 years for 216 cases of type 2 diabetes. PAI-1 4G/4G homozygotes (genotype frequency, 27.4%) were not at significantly (p > 0.05) increased risk of incident diabetes compared with 5G allele carriers and did not have elevated levels of diabetes-related quantitative traits including BMI, fasting plasma glucose, or fasting insulin. In proportional hazards regression models accounting for correlation among siblings, with the 5G/5G genotype as the referent, the hazard ratio for incident diabetes for 4G/5G carriers was 0.93 (95% confidence interval, 0.68 to 1.28) and for 4G/4G carriers was 1.20 (95% confidence interval, 0.83 to 1.92). Results were not altered by further adjustment for sex or levels of BMI, triglycerides, or PAI-1. We conclude that the PAI-1 4G/5G polymorphism is not an important genetic risk factor for type 2 diabetes in this community-based sample. Elevated PAI-1 levels may be associated with an increased risk for diabetes as a marker for underlying endothelial dysfunction rather than by a direct effect of genetically mediated elevated levels.

Adult↗
PubMed2005

Increased small low-density lipoprotein particle number: a prominent feature of the metabolic syndrome in the Framingham Heart Study.

BACKGROUND: Levels of LDL cholesterol (LDL-C) are frequently not elevated in individuals with the metabolic syndrome (MetSyn). However, the atherogenic potential of LDL may depend on the number and size of LDL particles in addition to the cholesterol content of LDL. METHODS AND RESULTS: We examined the sex-specific cross-sectional relations of small LDL particle number (determined by nuclear magnetic resonance spectroscopy) to the presence of MetSyn and its components in 2993 Framingham Heart Study participants (mean age, 51 years; 53% women) without cardiovascular disease (CVD) and the relations of small LDL particle number to CVD incidence in people with MetSyn. The MetSyn (> or =3 of 5 traits as defined by the National Cholesterol Education Adult Treatment Panel III) was present in 27% of men and 17% of women. In both sexes, small LDL particle number increased from 0 to 5 MetSyn traits, a pattern partly accounted for by strong correlations between small LDL particle number and serum triglycerides (r=0.61, P<0.0001) and HDL-C (r=-0.55, P<0.0001). Compared with participants without the MetSyn, those with the MetSyn had a higher CVD event rate. However, among participants with the MetSyn, CVD rates were similar for groups with an elevated versus a lower number of small LDL particles (defined by the sex-specific median). CONCLUSIONS: Small LDL particle number is elevated in the MetSyn, increases with the number of MetSyn components, and most prominently is correlated with triglycerides and HDL-C. Whereas increased small LDL particle number identified the MetSyn with high sensitivity, a higher small LDL particle number was not associated with greater CVD event rates in people with the MetSyn.

Adult↗
PubMed2005

Aging syndrome genes and premature coronary artery disease.

BACKGROUND: Vascular disease is a feature of aging, and coronary vascular events are a major source of morbidity and mortality in rare premature aging syndromes. One such syndrome is caused by mutations in the lamin A/C (LMNA) gene, which also has been implicated in familial insulin resistance. A second gene related to premature aging in man and in murine models is the KLOTHO gene, a hypomorphic variant of which (KL-VS) is significantly more common in the first-degree relatives of patients with premature coronary artery disease (CAD). We evaluated whether common variants at the LMNA or KLOTHO genes are associated with rigorously defined premature CAD. METHODS: We identified 295 patients presenting with premature acute coronary syndromes confirmed by angiography. A control group of 145 patients with no evidence of CAD was recruited from outpatient referral clinics. Comprehensive haplotyping of the entire LMNA gene, including the promoter and untranslated regions, was performed using a combination of TaqMan probes and direct sequencing of 14 haplotype-tagging single nucleotide polymorphisms (SNPs). The KL-VS variant of the KLOTHO gene was typed using restriction digest of a PCR amplicon. RESULTS: Two SNPs that were not in Hardy Weinberg equilibrium were excluded from analysis. We observed no significant differences in allele, genotype or haplotype frequencies at the LMNA or KLOTHO loci between the two groups. In addition, there was no evidence of excess homozygosity at the LMNA locus. CONCLUSION: Our data do not support the hypothesis that premature CAD is associated with common variants in the progeroid syndrome genes LMNA and KLOTHO.

Aging, Premature↗
PubMed2005

Comprehensive survey of common genetic variation at the plasminogen activator inhibitor-1 locus and relations to circulating plasminogen activator inhibitor-1 levels.

BACKGROUND: Using a linkage disequilibrium (LD)-based approach, we sought to comprehensively define common genetic variation at the plasminogen activator inhibitor-1 (PAI-1) locus and relate common single nucleotide polymorphisms (SNPs) and haplotypes to plasma PAI-1 levels. METHODS AND RESULTS: In reference pedigrees, we defined LD structure across a 50-kb genomic segment spanning the PAI-1 locus via a dense SNP map (1 SNP every 2 kb). Eighteen sequence variants that capture underlying common genetic variation were genotyped in 1328 unrelated Framingham Heart Study participants who had plasma PAI-1 antigen levels measured. Regression analyses were used to examine associations of individual SNPs and of inferred haplotypes with multivariable-adjusted PAI-1 levels. Two genetic variants, SNP rs2227631 and the 4G/5G polymorphism, were strongly associated (P<0.0001) with PAI-1 levels. SNP rs2227631 is in tight LD (D'=0.97, r2=0.78) with the 4G/5G polymorphism, which makes it difficult to distinguish which of these 2 polymorphisms is responsible for the association with PAI-1 levels. In stepwise analysis considering all polymorphisms tested, 3 SNPs, rs2227631 (or the correlated 4G/5G polymorphism), rs6465787, and rs2227674, each explained 2.5%, 1%, and 1%, respectively, of the residual variance in multivariable-adjusted PAI-1 levels (stepwise P<0.0001, P=0.04, and P=0.03, respectively). A single common haplotype, at 50% frequency among Framingham Heart Study participants, was strongly associated with higher PAI-1 levels (haplotype-specific P=0.00001). The susceptibility haplotype harbors the minor alleles of SNP rs2227631 and the 4G/5G polymorphism. CONCLUSIONS: Three sequence variants at the PAI-1 locus, in sum, explain approximately 5% of the residual variance in multivariable-adjusted PAI-1 levels. For quantitative cardiovascular traits such as circulating biomarkers, defining LD structure in a candidate gene followed by association analyses with both SNPs and haplotypes is an effective approach to localize common susceptibility alleles.

Aged↗
PubMed2005

Common genetic variation at the endothelial nitric oxide synthase locus and relations to brachial artery vasodilator function in the community.

BACKGROUND: Sequence variants at the endothelial nitric oxide synthase (NOS3) locus have been associated with endothelial function measures, but replication has been limited. METHODS AND RESULTS: In reference pedigrees, we characterized linkage disequilibrium structure at the NOS3 locus using 33 common single nucleotide polymorphisms (SNPs). Eighteen SNPs that capture underlying common variation were genotyped in unrelated Framingham Heart Study participants (49.5% women; mean age, 62 years) with measured brachial artery flow-mediated dilation (n=1446) or hyperemic flow velocity (n=1043). Within 3 defined blocks of strong linkage disequilibrium that spanned NOS3, 11 SNPs captured >80% of common haplotypic variation. Among men, there were nominally significant associations between 8 NOS3 SNPs (minimum P=0.002) and between haplotypes (minimum P=0.002) and either flow-mediated dilation or hyperemic flow velocity. In women, we did not observe significant associations between NOS3 SNPs or haplotypes and endothelial function measures. To correct for multiple testing, we constructed 1000 bootstrapped null data sets and found that empirical probability values exceeded 0.05 for both phenotypes. CONCLUSIONS: A parsimonious set of SNPs captures common genetic variation at the NOS3 locus. A conservative interpretation of our results is that, accounting for multiple testing, we did not observe statistically significant relations between NOS3 sequence variants and endothelial function measures in either sex. The nominal associations of select NOS3 variants with endothelial function in men (unadjusted for multiple testing) should be viewed as hypothesis-generating observations and may merit testing in other cohorts and experimental designs.

Aged↗
PubMed2005

CCL2 polymorphisms are associated with serum monocyte chemoattractant protein-1 levels and myocardial infarction in the Framingham Heart Study.

BACKGROUND: Monocyte chemoattractant protein-1 (MCP-1) is a chemokine strongly implicated in promoting atherosclerosis in animal models, but human genetic evidence is contradictory. METHODS AND RESULTS: We analyzed the association of genetic variation in the MCP-1 gene (CCL2) with prevalent myocardial infarction and serum MCP-1 levels in the community-based Framingham Heart Study Offspring Cohort (50% women; mean age, 62 years). MCP-1 levels and CCL2 genotypes were determined in 3236 and 1797 individuals, respectively. Significant clinical correlates of MCP-1 levels were age, cigarette smoking, triglycerides, body mass index, and waist-to-hip ratio. The MCP-1-2578G allele located in the CCL2 regulatory region was significantly associated with both higher serum MCP-1 levels in a recessive genetic model (358+/-10 versus 328+/-3 pg/mL; P=0.002) and higher prevalence of myocardial infarction in a dominant genetic model (adjusted odds ratio, 2.0; 95% CI, 1.2 to 3.3; P=0.005). We also defined the linkage disequilibrium structure at the CCL2 locus and observed 6 common haplotypes in whites. We performed haplotype-based association analysis and found that only the most frequent haplotype, defined by the MCP-1-2578G allele, was associated with prevalent MI. CONCLUSIONS: Our data are consistent with the hypothesis that MCP-1 is involved in the pathogenesis of human atherosclerosis and myocardial infarction.

Aged↗
PubMed2005

Clinical and genetic correlates of serum aldosterone in the community: the Framingham Heart Study.

BACKGROUND: We investigated the environmental and genetic sources of interindividual variability in serum aldosterone level in a large, community-based sample. METHODS: We examined the relation of serum aldosterone to vascular risk factors, urine sodium, and candidate single nucleotide polymorphisms in 2891 Framingham Offspring Study participants (53.2% women, mean age 59 years) using multivariable linear regression. Multivariable logistic regression was used to identify predictors of high (top quartile) and low (lowest quartile) serum aldosterone values. We estimated heritability of serum aldosterone via variance-component methods and evaluated linkage via a 10-cM-density genome scan. RESULTS: Clinical variables related to higher serum aldosterone level included female sex, diuretic treatment, and a higher total/high density lipoprotein cholesterol ratio. A high urinary sodium excretion, postmenopausal status (without hormone replacement therapy), increased pulse pressure, and prevalent cardiovascular disease were related to lower serum aldosterone values. Urinary sodium was the strongest correlate of serum aldosterone (R2= 10%). Serum aldosterone levels did not differ by genotype in the aldosterone synthase (CYP11B2c.1-344C>T) and the mineralocorticoid receptor (NR3C2c.754A>G) genes. The estimated heritability of serum aldosterone was 0.10. No chromosomal region attained a log-of-the-odds score >1 in multipoint linkage analysis. CONCLUSIONS: We observed a complex relation between serum aldosterone and vascular risk factors. The genetic contribution to serum aldosterone level was modest.

Adult↗
PubMed2003

Clinician update: direct thrombin inhibitors in acute coronary syndromes.

Antithrombotic therapy has become the cornerstone of the treatment for atherosclerotic cardiovascular disease. Unfractionated heparin (UFH) has been the thrombin inhibitor of choice for decades. UFH, however, has its deficiencies. To overcome these problems several direct thrombin inhibitors (DTIs) have been developed. These agents are capable of inactivating clot-bound thrombin more efficiently, and provide more predictable and safer anticoagulation in patients with of acute coronary syndromes (ACS). The initial studies of hirudin and bivalirudin in the clinical settings of acute myocardial infarction (AMI), unstable angina (UA) and percutaneous coronary interventions (PCI) conducted in the early 1990s proved to be disappointing. As the knowledge of more appropriate use of these drugs progressed, there is a renewed interest in DTIs. Herein we will review the clinical studies assessing hirudin, bivalirudin and argatroban in the settings of AMI, UA and PCI.

Acute Disease↗
PubMed2003

Off-pump coronary bypass grafting is associated with less myocardial injury than coronary bypass surgery with cardiopulmonary bypass.

BACKGROUND: Excessive myocardial necrosis following coronary artery bypass grafting is associated with adverse outcome. The present study was designed to assess the extent of myocardial injury after conventional coronary artery bypass grafting with cardio pulmonary bypass (ONCAB) compared with off-pump coronary artery bypass (OPCAB). METHODS: Measurements of serum cardiac troponin T (TnT) were obtained in 137 consecutive, unselected patients who underwent coronary artery bypass grafting. Serial blood sampling was performed at 3 time intervals after surgery: immediately postoperatively, 6 to 12 hours postoperatively, and 18 to 24 hours postoperatively. RESULTS: ONCAB patients totaled 122, and OPCAB patients numbered 15. Ten patients in the ONCAB group suffered perioperative complications, compared with no patients in the OPCAB group. At each time point examined, OPCAB patients exhibited significantly less release of TnT than ONCAB patients (immediately postoperative TnT, 1.99 +/- 4.75 ng/mL versus 0.20 +/- 0.32 ng/mL, P =.004; 6- to 12-hour TnT, 2.28 +/- 3.66 ng/mL versus 0.37 +/- 0.32 ng/mL, P =.001; and 18- to 24-hour TnT 1.59 +/- 3.49 ng/mL versus 0.30 +/- 0.32 ng/mL, P =.01). When ONCAB patients with perioperative ischemic complications were excluded, the differences between the 2 groups remained. The OPCAB patients still demonstrated less TnT release, typically 5- to 6-fold less than for ONCAB patients. CONCLUSIONS: The nearly 6-fold reduction of postoperative TnT associated with OPCAB suggests that off-pump surgery may offer superior cardioprotection than coronary artery bypass grafting with conventional cardiopulmonary bypass. \par

Adolescent↗
PubMed2002

A comparison of cardiac troponin T and creatine kinase-MB for patient evaluation after cardiac surgery.

OBJECTIVES: The aim of this study was to assess the role of serum markers of myocardial necrosis after cardiac surgery. BACKGROUND: The role of serum troponin T (TnT) and creatine kinase-MB (CK-MB) for the risk stratification of patients after cardiac surgery remains undefined. METHODS: Serum levels of TnT and CK-MB were measured from 224 patients every 8 h after cardiac surgery. The results of serum cardiac marker testing were correlated with adverse events, including new myocardial infarction (MI), cardiogenic shock or death. Univariable analysis identified factors predictive of complications, while stepwise logistic regression identified independent predictors of postoperative complications. RESULTS: Cardiac marker elevation was universal after cardiac surgery. At all time points measured, compared with those patients without complications, the TnT levels from patients with complications were more significantly elevated (all: p < 0.0005). In contrast, among identically timed specimens, the levels of CK-MB from complicated patients were less reliably discriminatory. Multivariable analysis suggested that a TnT level in the highest quintile (> or = 1.58 ng/ml) was the strongest predictor of complications, including death (post-op, odds ratio [OR] = 31.0, 95% confidence interval [CI] = 3.67 to 263.1, p = 0.002) or shock (post-op: OR = 18.9, 95% CI = 2.29 to 156.1, p = 0.006; 18 h to 24 h: OR = 30.7, 95% CI = 3.75 to 250.7, p = 0.001), as well as the composite end points of death/MI (18 h to 24 h: OR = 60.1, 95% CI = 7.34 to 492.1, p < 0.0005), shock/MI (post-op: OR = 23.3, 95% CI = 2.82 to 191.4, p = 0.003; 18 h to 24 h: OR = 37.8, 95% CI = 4.66 to 307.3, p = 0.001) or death/shock/MI (post-op: OR = 20.0, 95% CI = 2.81 to 142.0, p = 0.003; 18 h to 24 h: OR = 67.4, 95% CI = 6.96 to 652.3, p < 0.0005). In contrast, in the presence of TnT, the results of CK-MB measurement added no independent prognostic information. CONCLUSIONS: Troponin T is superior to CK-MB for the prediction of impending complications after cardiac surgical procedures.

Adolescent↗