Biomedical subjects

Martin G Larson

Publications and source records attributed to Martin G Larson.

At least 37 records · Page 2Linked to original sources

PubMed2006

Association of educational level with inflammatory markers in the Framingham Offspring Study.

Socioeconomic position consistently predicts coronary heart disease; however, the biologic mechanisms that may mediate this association are not well understood. The objective of this study was to determine whether socioeconomic position (measured as educational level) is associated with inflammatory risk factors for coronary heart disease, including C-reactive protein, interleukin-6, soluble intercellular adhesion molecule-1, monocyte chemoattractant protein-1, and P-selectin. The study sample included 2,729 participants (53.4% women; mean age, 62 +/- 10 years) from the US Framingham Offspring Study cohort who attended examination cycles 3 (1984-1987) and 7 (1998-2001) and provided educational attainment data. Inflammatory markers were measured in fasting serum samples. Multivariable linear regression analyses were performed, adjusting for potential confounders including age, sex, and clinical risk factors. In age- and sex-adjusted analyses, educational attainment was significantly inversely associated with C-reactive protein (p < 0.0001), interleukin-6 (p < 0.0001), soluble intercellular adhesion molecule-1 (p < 0.0001), and monocyte chemoattractant protein-1 (p = 0.0004). After further adjustment for clinical risk factors, educational level remained significantly associated with C-reactive protein (p = 0.0002), soluble intercellular adhesion molecule-1 (p = 0.01), and monocyte chemoattractant protein-1 (p = 0.01). In conclusion, educational attainment is associated with inflammatory risk factors for coronary heart disease. The association provides evidence suggestive of a biologic pathway by which socioeconomic position may predispose to coronary heart disease.

Biomarkers↗

PubMed2006

Cross-sectional correlates of serum heat shock protein 70 in the community.

BACKGROUND: Recent studies of referral samples suggest that heat shock proteins play a key role in the pathogenesis of high BP and cardiovascular diseases (CVD) including heart failure. It is unclear whether circulating heat shock protein 70 (HSP70) levels are related to CVD risk factors, echocardiographic indexes of left ventricular (LV) remodeling, and prevalent CVD in the population. METHODS: We evaluated the cross-sectional relations of serum HSP70 to established CVD risk factors (including hypertension), markers of oxidative stress (urinary 8-epi-PGF(2alpha)) and inflammation (plasma interleukin-6, C-reactive protein, monocyte chemoattractant protein-1 MCP-1, and soluble intercellular adhesion molecule sICAM-1), echocardiographic LV dimensions and prevalent CVD in 456 Framingham Offspring Study participants (mean age 61 years, 42% women). RESULTS: In multivariable analyses, serum HSP70 was not associated with age, sex, vascular risk factors (including hypertension), echocardiographic LV mass or prevalent CVD. Also, serum HSP70 was not related to any of the biomarkers evaluated (p> or = 0.10 for all). CONCLUSIONS: In our community-based sample, serum HSP70 was similar in men and women, and not significantly related to traditional or novel risk factors, to LV mass or to prevalent CVD. Our data suggest that blood levels may not adequately reflect the important role of heat shock proteins in prevalent CVD.

Biomarkers↗

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↗

PubMed2006

Obstructive sleep apnea and plasma natriuretic peptide levels in a community-based sample.

STUDY OBJECTIVES: We hypothesized that alterations in cardiac hemodynamics associated with obstructive sleep apnea-hypopnea (OSAH) would be reflected in higher natriuretic peptide levels. We examined the association of OSAH with natriuretic peptides in a community-based sample. DESIGN: Cross-sectional, retrospective, observational study. SETTING: Framingham Heart Study Offspring Cohort and Sleep Heart Health Study. PARTICIPANTS: Community-based sample of 623 individuals. MEASUREMENTS: Full-montage home polysomnography was used to determine apnea-hypopnea index (AHI) and percentage of time with an oxyhemoglobin saturation < 90% (PctLt90). Sensitive immunoradiometric assays were used to measure plasma B-type (BNP) and N-terminal pro-atrial natriuretic peptide (NT-ANP). Multivariable regression was used to examine the relations between natriuretic peptides and indicators of OSAH, adjusting for age, sex, body mass index, and clinical covariates. RESULTS: No statistically significant relations between OSAH indices and BNP were observed in the multivariable model. Compared with an AHI < 5, relative levels of 1.20, 0.88, and 0.91 were observed forAHI categories 5-15, 15-30, >30 events per hour, respectively. For NT-ANP, no significant relations were seen with AHI in the multivariable model (relative levels of 0.98, 0.91, and 0.90). An inverse association was observed between NT-ANP and PctLt90 in age- and sex-adjusted models (relative levels of 0.93, 0.87, and 0.80), although this association became statistically nonsignificant after adjusting for body mass index. CONCLUSION: Lack of association of natriuretic peptides with OSAH indices suggests that undiagnosed OSAH may not be associated with major alterations in left ventricular function, as reflected in morning natriuretic peptide levels.

Atrial Fibrillation↗

PubMed2005

Cross-sectional association of kidney function with valvular and annular calcification: the Framingham heart study.

Valvular calcification is common in the setting of end-stage kidney disease and is associated with increased risks for cardiovascular disease events. It is unknown whether the prevalence of valvular calcification is increased in milder kidney disease after accounting for cardiovascular risk factors. Participants who attended the sixth examination of the Framingham Offspring Study (1995 to 1998) were eligible. Kidney function was estimated by GFR using the simplified Modification of Diet in Renal Disease Study equation. Mitral annular calcification (MAC), aortic sclerosis, and aortic annular calcification were assessed by two-dimensional echocardiography. Logistic regression was used to examine the odds of valvular calcification among participants with chronic kidney disease (CKD; GFR < 60 ml/min per 1.73 m(2)). A total of 3047 participants (52% women; mean age 59 +/- 10 yr) were available for analysis. CKD was present in 8.6% (n = 262) of the sample. Among participants with valve/annular calcification (n = 284; 9.3%), 20% had CKD, compared with 7% in patients without valvular calcification. After adjustment for age, gender, systolic and diastolic BP, hypertension treatment, total/HDL cholesterol, body mass index, diabetes, smoking status, and cardiovascular disease, participants with CKD had a 60% increased odds of MAC (odds ratio 1.6; 95% confidence interval 1.03 to 2.5). There was no significant association between CKD and either aortic sclerosis or aortic annular calcification (odds ratio 1.1 and 1.1, respectively). After age and gender adjustment, the combination of both CKD and MAC was associated with a three-fold increased risk for death compared with those with neither condition (P = 0.0004). In the community, CKD is associated with presence of MAC before the onset of ESRD. Further research is warranted to understand whether traditional and novel vascular risk factor burden, as well as metabolic derangements found in early kidney disease, can account for the CKD-MAC association.

Aged↗

PubMed2005

Cross-sectional relations of peripheral microvascular function, cardiovascular disease risk factors, and aortic stiffness: the Framingham Heart Study.

BACKGROUND: Aortic stiffness and small-artery structure and function share various risk factors; however, relations between these 2 measures of vascular function are complex and incompletely understood. METHODS AND RESULTS: We examined hyperemic forearm blood flow, an indicator of microvascular structure and function, and aortic stiffness in 2045 participants (1107 women, mean age 61+/-9 years) in the Framingham Heart Study offspring cohort. Using arterial tonometry, we evaluated 3 measures of aortic stiffness: brachial pulse pressure; carotid-femoral pulse wave velocity (CFPWV), which is related directly to aortic wall stiffness; and forward pressure wave amplitude (Pf), which is related directly to aortic wall stiffness and inversely to aortic diameter. Using high-resolution ultrasound and Doppler, we evaluated brachial artery diameter, blood flow, and forearm vascular resistance (FVR) at baseline and during reactive hyperemia after 5 minutes of forearm ischemia. In multivariable models that adjusted for cardiovascular disease risk factors, local brachial pulse pressure, CFPWV, and Pf, considered separately, were associated with increased baseline and hyperemic FVR (P<0.001). In models that further adjusted for mean arterial pressure, each measure of aortic stiffness was associated with reduced hyperemic flow (P<0.001). In risk factor-adjusted models that simultaneously considered CFPWV and Pf, both were associated with increased FVR at baseline (P<0.01) and during hyperemia (P<0.001). CONCLUSIONS: Our findings indicate that abnormal aortic stiffness and increased pressure pulsatility are associated with blunted microvascular reactivity to ischemic stress that is in excess of changes attributable to conventional cardiovascular disease risk factors alone, including mean arterial pressure.

Adult↗

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

Heritability and a genome-wide linkage scan for arterial stiffness, wave reflection, and mean arterial pressure: the Framingham Heart Study.

BACKGROUND: Arterial stiffness and mean arterial pressure variably contribute to systolic hypertension and increased cardiovascular risk. However, few prior community-based studies have evaluated the genetics of arterial stiffness and separate mean and pulsatile components of blood pressure. METHODS AND RESULTS: Using arterial tonometry, we evaluated heritability and linkage of forward and reflected wave amplitude, mean arterial pressure, and carotid-femoral pulse wave velocity (CFPWV) in 1480 participants representing 817 pedigrees in the Framingham Study offspring cohort. In 204 families with tonometry data, a genome-wide scan was performed with microsatellite markers that covered the genome at 10-cM intervals. Heritability estimates were moderate for reflected wave amplitude (h2=0.48), forward wave amplitude (h2=0.21), CFPWV (h2=0.40), and mean arterial pressure (h2=0.33). Variance components linkage analysis identified 2 regions of linkage for reflected wave amplitude: chromosome 4 at 181 cM (logarithm of odds [LOD]=4.93, permuted P=0.002) and chromosome 8 at 33 cM (LOD=3.27, permuted P=0.058). There was 1 region of linkage for forward wave amplitude on chromosome 7 at 174 cM (LOD=2.88, permuted P=0.017). There were several regions of suggestive linkage for CFPWV: chromosome 2 at 94 cM (LOD=2.46), chromosome 7 at 29 cM (LOD=2.50), chromosome 13 at 108 cm (LOD=2.10), and chromosome 15 at 108 cM (LOD=2.48). There was 1 region of suggestive linkage for mean arterial pressure on chromosome 1 at 192 cM (LOD=2.18). CONCLUSIONS: Arterial stiffness measures and mean and pulsatile components of blood pressure are heritable and appear to have genetic determinants that may be linked to separate genetic loci in humans.

Aged↗

PubMed2005

A comparison of death certificate out-of-hospital coronary heart disease death with physician-adjudicated sudden cardiac death.

The number of deaths due to out-of-hospital coronary heart disease as determined by death certificates was compared with the number physician-adjudicated sudden cardiac deaths in the Framingham Heart Study from 1950 to 1999. Out-of-hospital coronary heart disease deaths overestimated sudden cardiac death by 47%, suggesting that out-of-hospital coronary heart disease death rates derived from death certificates should be interpreted with caution.

Aged↗

PubMed2005

Genome scan of systemic biomarkers of vascular inflammation in the Framingham Heart Study: evidence for susceptibility loci on 1q.

Vascular inflammation plays a central role in atherosclerosis and inflammatory biomarkers predict risk of cardiovascular disease (CVD). Thus, finding genes that influence systemic levels of inflammatory biomarkers may provide insights into genetic determinants of vascular inflammation and CVD. We conducted variance-component linkage analyses of blood levels of four biomarkers of vascular inflammation [C-reactive protein (CRP), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), soluble intercellular adhesion molecule-1 (sICAM-1)] in 304 extended families from the Framingham Heart Study, using data from a 10cM genome scan. We computed p-values by a permutation approach. Heritability estimates ranged from 14% (IL-6) to 44% (MCP-1) after log transforming and adjusting for covariates. Significant linkage to MCP-1 was found on chromosome 1 (LOD=4.27 at 186cM; genome-wide p=0.005), in a region containing inflammatory candidate genes such as SELE, SELP (E- and P-selectin) and CRP. Other linkage peaks with LOD scores >2 were found for MCP-1 on chromosome 1 (LOD=2.04 at 16cM; LOD=2.34 at 70cM) and chromosome 17 (LOD=2.44 at 22cM) and for sICAM-1 on chromosome 1 at 229cM (LOD=2.09) less than 5cM from the interleukin-10 (IL10) gene. Multiple genes on chromosome 1 may influence inflammatory biomarker levels and may have a potential role in development of CVD.

Aged↗

PubMed2005

Cross-sectional relations of electrocardiographic QRS duration to left ventricular dimensions: the Framingham Heart Study.

OBJECTIVES: The goal of this study was to assess the relations of electrocardiographic QRS duration to left ventricular (LV) measurements in individuals without heart failure (HF) or prior myocardial infarction (MI). BACKGROUND: Increased electrocardiographic QRS duration (>/=120 ms) is a marker of ventricular dyssynchrony. METHODS: We evaluated the relations of maximal electrocardiographic QRS duration to echocardiographic LV dimensions in 4,534 Framingham Heart study participants (mean age 54 years, 57% women) without prior HF or MI. QRS duration was analyzed as a continuous variable and as categories (<100, 100 to 119, and >/=120 ms). RESULTS: In linear regression models, LV mass, end-diastolic dimension, and septal and posterior wall thicknesses were positively related to log-QRS duration, whereas fractional shortening (FS) was inversely related (p < 0.001). There was a significant trend for increasing LV mass and dimensions, and decreasing FS across categories of QRS duration (p < 0.001). Left bundle branch block was associated with higher LV mass and lower FS compared with a normal QRS duration (p < 0.001). CONCLUSIONS: In our community-based sample of individuals free of HF and MI, increasing electrocardiographic QRS duration was positively related to LV mass and dimensions, and inversely associated with LV FS. Additional investigations are warranted to elucidate the mechanisms underlying the observed associations.

Adult↗

PubMed2005

Predictors of new-onset diastolic and systolic hypertension: the Framingham Heart Study.

BACKGROUND: Factors leading differentially to the development of isolated diastolic (IDH), systolic-diastolic (SDH), and isolated systolic (ISH) hypertension are poorly understood. We examined the relations of blood pressure (BP) and clinical risk factors to the new onset of the 3 forms of hypertension. METHODS AND RESULTS: Participants in the Framingham Heart Study were included if they had undergone 2 biennial examinations between 1953 and 1957 and were free of antihypertensive therapy and cardiovascular disease. Compared with optimal BP (SBP <120 and DBP <80 mm Hg), the adjusted hazard ratios (HRs) for developing new-onset IDH over the ensuing 10 years were 2.75 for normal BP, 3.29 for high-normal BP (both P<0.0001), 1.31 (P=0.40) for SDH, and 0.61 (P=0.36) for ISH. The HRs of developing new-onset SDH were 3.32, 7.96, 7.10, and 23.12 for the normal BP, high-normal BP, ISH, and IDH groups, respectively (all P<0.0001). The HRs of developing ISH were 3.26 for normal and 4.82 for high-normal BP (both P<0.0001), 1.39 (P=0.24) for IDH, and 1.69 (P<0.01) for SDH. Increased body mass index (BMI) during follow-up predicted new-onset IDH and SDH. Other predictors of IDH were younger age, male sex, and BMI at baseline. Predictors of ISH included older age, female sex, and increased BMI during follow-up. CONCLUSIONS: Given the propensity for increased baseline BMI and weight gain to predict new-onset IDH and the high probability of IDH to transition to SDH, it is likely that IDH is not a benign condition. ISH arises more commonly from normal and high-normal BP than from "burned-out" diastolic hypertension.

Adult↗

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↗

PubMed2005

QT interval is a heritable quantitative trait with evidence of linkage to chromosome 3 in a genome-wide linkage analysis: The Framingham Heart Study.

OBJECTIVES: To identify genomic regions linked to QT interval duration in an unselected population. BACKGROUND: QT interval prolongation is associated with increased risk of sudden cardiac death and coronary heart disease and may result from acquired conditions or inherited ion channel defects. The influence of genetic variants on QT interval length in apparently healthy individuals is uncertain. METHODS: We studied subjects from the Framingham Heart Study in whom 12-lead ECGs were available from regular clinic examinations. QT, QT-peak, and RR intervals were measured using digital calipers. A 10-centiMorgan (cM) density genome-wide scan was performed in a subset of the largest families having at least two members with ECG phenotypes (326 families). Variance components methods (Genehunter) were used. RESULTS: Evidence was observed for significant heritability of the QT interval (h(2) 0.35; 95% CI, 0.29-0.41), QT-peak interval (h(2) 0.37; 95% CI, 0.29-0.45), and calculated JT interval (h(2) 0.25; 95% CI, 0.19-0.31). In the genome-wide linkage analysis, we found suggestive evidence for linkage of the QT interval 19 to 48 cM from the tip of the short arm of chromosome 3 (maximum two-point LOD score 3.00, maximum multipoint LOD score 2.71). After fine-mapping with seven microsatellite markers, the peak multipoint LOD score rose to 2.84 at 24.4 cM. The region of linkage contains potassium and sodium channel genes, including the SCN5A gene, which has been implicated in one form of the long QT syndrome and in the Brugada syndrome. CONCLUSIONS: QT and related ECG intervals are heritable traits in a large unselected population. We provide suggestive evidence for a quantitative trait locus on chromosome 3 influencing QT interval duration. Further studies are warranted to identify genes that influence QT interval variation and to determine the role of heritable factors in life-threatening QT prolongation.

Aged↗

PubMed2005

Variation in estrogen-related genes and cross-sectional and longitudinal blood pressure in the Framingham Heart Study.

OBJECTIVE: To examine the association between variation in estrogen-related genes and cross-sectional and longitudinal blood pressure in men and women. DESIGN: In 1780 unrelated members of the community-based Framingham Heart Study offspring cohort, systolic blood pressure and diastolic blood pressure were measured over a total of six examination cycles encompassing 24 years of follow-up. Multivariate regression analyses were used to assess the relation between untreated cross-sectional and longitudinal blood pressure and polymorphisms at the estrogen receptor-alpha (ESR1), estrogen receptor-beta (ESR2), aromatase (CYP19A1), and nuclear receptor coactivator 1 (NCOA1) genes after adjustment for common risk factors. RESULTS: In men, systolic blood pressure and pulse pressure (systolic blood pressure minus diastolic blood pressure) were associated with two polymorphisms in ESR1, while pulse pressure was also associated with variations in NCOA1 and CYP19A1. Polymorphisms in ESR1, CYP19A1, and NCOA1 were associated with diastolic blood pressure in women. CONCLUSIONS: Although the underlying relations between genes involved in estrogen action and hypertension remain to be completely understood, our findings provide suggestive evidence of gender-specific contributions of estrogen-related genes to blood pressure variation. As no correction for multiple testing was performed in the analyses, we view these results as suggestive and not definitive. Further studies are warranted to confirm these results using a comprehensive set of polymorphisms in order to shed more light on the involvement of estrogen in blood pressure regulation.

Aromatase↗

PubMed2005

Glycemic status and development of kidney disease: the Framingham Heart Study.

OBJECTIVE: Diabetes is a major risk factor for the development of kidney disease and is the leading cause of end-stage renal disease in the U.S. Whether pre-diabetes is associated with the development of kidney disease is unclear. RESEARCH DESIGN AND METHODS: Subjects free of chronic kidney disease (CKD) were drawn from the Framingham Heart Study offspring cohort (1991-1995), given an oral glucose tolerance test, and followed for an average of 7 years for development of CKD (glomerular filtration rate [GFR] of <59 ml/min per 1.73 m2 in women and <64 ml/min per 1.73 m2 in men). Multivariable logistic regression models, adjusted for cardiovascular disease risk factors including age, sex, hypertension, smoking, BMI, total and HDL cholesterol levels, and prevalent myocardial infarction or congestive heart failure, were used to estimate the odds of patients developing kidney disease among glycemic categories. RESULTS: Of 2,398 subjects (53% women; mean age 54 years), 63% were normoglycemic, 29% had impaired fasting glucose (IFG) or impaired glucose tolerance (IGT), 3.4% were newly diabetic, and 4.6% had known diabetes. By glycemic category, mean GFR at follow-up was 87, 85, 82, and 78 ml/min per 1.73 m2, respectively. The fully adjusted odds of developing CKD were 0.98 (95% CI 0.67-1.45), 1.71 (95% CI 0.83-3.55), and 1.93 (95% CI 1.06-3.49) among those with IFG or IGT, newly diagnosed diabetes, or known diabetes, respectively, compared with those who were normoglycemic at baseline. Among participants without diabetes, metabolic syndrome was not associated with kidney disease at follow-up (odds ratio 1.46, P = 0.06). CONCLUSIONS: Cardiovascular disease risk factors explain much of the relationship between prediabetes and the development of chronic kidney disease. Clinical trials are warranted to determine whether vascular risk factor modification can slow the decline of kidney function among those with pre-diabetes.

Adult↗