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1.  Statin Therapy and Levels of Hemostatic Factors in a Healthy Population: the Multi-Ethnic Study of Atherosclerosis 
HMG CoA reductase inhibitors (statins) reduce risk of venous thromboembolism (VTE) in healthy people. Statins reduce levels of inflammation biomarkers, however the mechanism for reduction in VTE risk is unknown. In a large cohort of healthy people, we studied associations of statin use with plasma hemostatic factors related to VTE risk.
Cross-sectional analyses were performed in the Multi-Ethnic Study of Atherosclerosis (MESA), a cohort study of 6814 healthy men and women age 45–84, free of clinical cardiovascular disease at baseline; 1001 were using statins at baseline. Twenty-three warfarin users were excluded. Age, race, and sex-adjusted mean hemostatic factor levels were compared between statin users and nonusers, and multivariable linear regression models were used to assess associations of statin use with hemostasis factors, adjusted for age, race/ethnicity, education, income, hormone replacement therapy (in women), and major cardiovascular risk factors.
Participants using statins had lower adjusted levels of D-dimer (−9%), C-reactive protein (−21%) and factor VIII (−3%) than non-users (p<0.05). Homocysteine and von Willebrand factor were non-significantly lower with statin use. Higher fibrinogen (2%) and PAI-1 (22%) levels were observed among statin users than nonusers (p<0.05). Further adjustment for LDL and triglyceride levels did not attenuate the observed differences in these factors by statin use.
Findings of lower D-dimer, factor VIII and C-reactive protein levels with statin use suggest hypotheses for mechanisms whereby statins might lower VTE risk. A prospective study or clinical trial linking these biochemical differences to VTE outcomes in statin users and nonusers is warranted.
PMCID: PMC3702638  PMID: 23565981
statins; thrombosis; risk factor; blood coagulation; inflammation; fibrinolysis
2.  DNA Methylation in an Enhancer Region of the FADS Cluster Is Associated with FADS Activity in Human Liver 
PLoS ONE  2014;9(5):e97510.
Levels of omega-6 (n-6) and omega-3 (n-3), long chain polyunsaturated fatty acids (LcPUFAs) such as arachidonic acid (AA; 20∶4, n-6), eicosapentaenoic acid (EPA; 20∶5, n-3) and docosahexaenoic acid (DHA; 22∶6, n-3) impact a wide range of biological activities, including immune signaling, inflammation, and brain development and function. Two desaturase steps (Δ6, encoded by FADS2 and Δ5, encoded by FADS1) are rate limiting in the conversion of dietary essential 18 carbon PUFAs (18C-PUFAs) such as LA (18∶2, n-6) to AA and α-linolenic acid (ALA, 18∶3, n-3) to EPA and DHA. GWAS and candidate gene studies have consistently identified genetic variants within FADS1 and FADS2 as determinants of desaturase efficiencies and levels of LcPUFAs in circulating, cellular and breast milk lipids. Importantly, these same variants are documented determinants of important cardiovascular disease risk factors (total, LDL, and HDL cholesterol, triglycerides, CRP and proinflammatory eicosanoids). FADS1 and FADS2 lie head-to-head (5′ to 5′) in a cluster configuration on chromosome 11 (11q12.2). There is considerable linkage disequilibrium (LD) in this region, where multiple SNPs display association with LcPUFA levels. For instance, rs174537, located ∼15 kb downstream of FADS1, is associated with both FADS1 desaturase activity and with circulating AA levels (p-value for AA levels = 5.95×10−46) in humans. To determine if DNA methylation variation impacts FADS activities, we performed genome-wide allele-specific methylation (ASM) with rs174537 in 144 human liver samples. This approach identified highly significant ASM with CpG sites between FADS1 and FADS2 in a putative enhancer signature region, leading to the hypothesis that the phenotypic associations of rs174537 are likely due to methylation differences. In support of this hypothesis, methylation levels of the most significant probe were strongly associated with FADS1 and, to a lesser degree, FADS2 activities.
PMCID: PMC4026313  PMID: 24842322
3.  Usefulness of Biventricular Volume as a Predictor of Mortality in Patients with Diabetes Mellitus (From the Diabetes Heart Study) 
The American journal of cardiology  2013;111(8):1152-1158.
Individuals with type 2 diabetes mellitus (DM) are at increased risk of cardiovascular disease (CVD) and mortality. Beyond traditional CVD risk factors, novel measures reflecting additional aspects of disease pathophysiology, such as biventricular volume (BiVV), may be useful for risk stratification. This study examined the relationship between BiVV and risk for mortality in European Americans with type 2 DM from the Diabetes Heart Study. BiVV was calculated from 771 non-contrast computed tomography scans performed to image coronary artery calcified plaque (CAC). Relationships between BiVV and traditional CVD risk factors were examined. Cox proportional hazards regression was performed to determine risk for mortality (all-cause and CVD-mortality) associated with increasing BiVV. Area under the curve analysis was used to assess BiVV utility in risk prediction models. During 8.4 ± 2.4 years (mean ± SD) of follow-up, 23% of the sample were deceased. In unadjusted analyses, BiVV was significantly associated with increasing body mass index, height, CAC, history of hypertension and prior myocardial infarction (p<0.0001–0.012). BiVV was significantly associated with all-cause (HR: 2.45; CI: 1.06–5.67; p=0.036) and CVD-mortality (HR: 4.36; CI: 1.36–14.03; p=0.014) in models adjusted for other known CVD risk factors. Area under the curve increased from 0.76 to 0.78 (p=0.04) and 0.74 to 0.77 (p=0.02) for all-cause and CVD-mortality on inclusion of BiVV. In conclusion, in the absence of echocardiography or other noninvasive imaging modalities to assess ventricular volumes, or when such methods are contra-indicated, BiVV from computed tomography may be considered as a tool for stratification of high-risk individuals, such as those with type 2 DM.
PMCID: PMC3618594  PMID: 23351459
cardiovascular disease; heart size; diabetes; risk-prediction
4.  Coronary Calcium Score Predicts Cardiovascular Mortality in Diabetes 
Diabetes Care  2013;36(4):972-977.
In type 2 diabetes mellitus (T2DM), it remains unclear whether coronary artery calcium (CAC) provides additional information about cardiovascular disease (CVD) mortality beyond the Framingham Risk Score (FRS) factors.
A total of 1,123 T2DM participants, ages 34–86 years, in the Diabetes Heart Study followed up for an average of 7.4 years were separated using baseline computed tomography scans of CAC (0–9, 10–99, 100–299, 300–999, and ≥1,000). Logistic regression was performed to examine the association between CAC and CVD mortality adjusting for FRS. Areas under the curve (AUC) with and without CAC were compared. Net reclassification improvement (NRI) compared FRS (model 1) versus FRS+CAC (model 2) using 7.4-year CVD mortality risk categories 0% to <7%, 7% to <20%, and ≥20%.
Overall, 8% of participants died of cardiovascular causes during follow-up. In multivariate analysis, the odds ratios (95% CI) for CVD mortality using CAC 0–9 as the reference group were, CAC 10–99: 2.93 (0.74–19.55); CAC 100–299: 3.17 (0.70–22.22); CAC 300–999: 4.41(1.15–29.00); and CAC ≥1,000: 11.23 (3.24–71.00). AUC (95% CI) without CAC was 0.70 (0.67–0.73), AUC with CAC was 0.75 (0.72–0.78), and NRI was 0.13 (0.07–0.19).
In T2DM, CAC predicts CVD mortality and meaningfully reclassifies participants, suggesting clinical utility as a risk stratification tool in a population already at increased CVD risk.
PMCID: PMC3609509  PMID: 23230101
5.  Admixture Mapping of Coronary Artery Calcified Plaque in African Americans with Type 2 Diabetes 
The presence and severity of coronary artery calcified plaque (CAC) differs markedly between individuals of African and European descent, suggesting that admixture mapping (AM) may be informative for identifying genetic variants associated with subclinical cardiovascular disease (CVD).
Methods and Results
AM of CAC was performed in 1,040 unrelated African Americans with type 2 diabetes mellitus from the African American-Diabetes Heart Study (AA-DHS), Multi-Ethnic Study of Atherosclerosis (MESA), and Family Heart Study (FamHS) using the Illumina custom ancestry informative marker (AIM) panel. All cohorts obtained computed tomography scanning of the coronary arteries using identical protocols. For each AIM, the probability of inheriting 0, 1, and 2 copies of a European-derived allele was determined. Linkage analysis was performed by testing for association between each AIM using these probabilities and CAC, accounting for global ancestry, age, gender and study. Markers on 1p32.3 in the GLIS1 gene (rs6663966, LOD=3.7), 1q32.1 near CHIT1 (rs7530895, LOD=3.1), 4q21.2 near PRKG2 (rs1212373, LOD=3.0) and 11q25 in the OPCML gene (rs6590705, LOD=3.4) had statistically significant LOD scores, while markers on 8q22.2 (rs6994682, LOD=2.7), 9p21.2 (rs439314, LOD=2.7), and 13p32.1 (rs7492028, LOD=2.8) manifested suggestive evidence of linkage. These regions were uniformly characterized by higher levels of European ancestry associating with higher levels or odds of CAC. Findings were replicated in 1,350 AAs without diabetes and 2,497 diabetic European Americans from MESA and the Diabetes Heart Study.
Fine mapping these regions will likely identify novel genetic variants that contribute to CAC and clarify racial differences in susceptibility to subclinical CVD.
PMCID: PMC3578054  PMID: 23233742
ancestry; cardiovascular disease risk factors; type 2 diabetes; admixture mapping
6.  Associations among Lung Function, Arterial Elasticity and Circulating Endothelial and Inflammation Markers: the Multi-Ethnic Study of Atherosclerosis 
Hypertension  2013;61(2):542-548.
A parallel physiologic pathway for elastic changes is hypothesized for declines in arterial elasticity and lung function. Endothelial dysfunction and inflammation could potentially decrease elasticity of both vasculature and lung tissue. We examined biomarkers, large (LAE) and small (SAE) arterial elasticity, and forced vital capacity (FVC) in a period cross-sectional design in the Multi-Ethnic Study of Atherosclerosis, which recruited 1,823 women and 1,803 men, age range 45–84 years, black, white, Hispanic, and Chinese, free of clinically recognized CVD. Radial artery tonometric pulse waveform registration was performed and LAE and SAE were derived from diastole. Spirometric data and markers of endothelial dysfunction and inflammation (soluble intracellular adhesion molecule-1, fibrinogen, hs-C-reactive protein, and interleukin-6) were obtained. Mean LAE was 13.7 ± 5.5 ml/mmHgx10 and SAE was 4.6 ± 2.6 ml/mmHgx100. Mean FVC was 3,192 ± 956.0 mL and FEV1 was 2,386 ± 734.5 mL. FVC was about 40 ± 5 mL higher per SD of SAE, stronger in men than women. The association was slightly weaker with LAE, with no sex interaction. After regression adjustment for demographic, anthropometric, and cardiovascular risk factors, the biomarkers tended to be related to reduced SAE and FVC, particularly in men. These biomarker associations suggest important CVD risk alterations that occur concurrently with lower arterial elasticity and lung function. The observed positive association of SAE with FVC and with FEV1 in middle-aged to older free-living people is consistent with the hypothesis of parallel physiologic pathways for elastic changes in the vasculature and in lung parenchymal tissue.
PMCID: PMC3586233  PMID: 23283358
arterial stiffness; endothelial markers; inflammatory markers; large and small artery elasticity; lung function; MESA Study
7.  Relationship of Flow-Mediated Arterial Dilation and Exercise Capacity in Older Patients With Heart Failure and Preserved Ejection Fraction 
Older heart failure patients with preserved ejection fraction (HFpEF) have severely reduced exercise capacity and quality of life. Both brachial artery flow-mediated dilation (FMD) and peak exercise oxygen uptake (peak VO2) decline with normal aging. However, uncertainty remains regarding whether FMD is reduced beyond the degree associated with normal aging and if this contributes to reduced peak VO2 in elderly HFpEF patients.
Sixty-six older (70 ± 7 years) HFpEF patients and 47 healthy participants (16 young, 25 ± 3 years, and 31 older, 70 ± 6 years) were studied. Brachial artery diameter was measured before and after cuff occlusion using high-resolution ultrasound. Peak VO2 was measured using expired gas analysis during upright cycle exercise.
Peak VO2 was severely reduced in older HFpEF patients compared with age-matched healthy participants (15.2 ± 0.5 vs 19.6 ± 0.6 mL/kg/min, p < .0001), and in both groups, peak VO2 was reduced compared with young healthy controls (28.5 ± 0.8 mL/kg/min; both p < .0001). Compared with healthy young participants, brachial artery FMD (healthy young, 6.13% ± 0.53%) was significantly reduced in healthy older participants (4.0 ± 0.38; p < .0002) and in HFpEF patients (3.64% ± 0.28%; p < .0001). However, FMD was not different in HFpEF patients compared with healthy older participants (p = .86). Although brachial artery FMD was modestly related to peak VO2 in univariate analyses (r = .19; p = .048), it was not related in multivariate analyses that accounted for age, gender, and body size.
These results suggest that endothelial dysfunction may not be a significant independent contributor to the severely reduced exercise capacity in elderly HFpEF patients.
PMCID: PMC3598353  PMID: 22522508
Exercise capacity; Aging; Flow-mediated dilation; Heart failure with preserved ejection fraction; Endothelial function
8.  Diagnostic Time Course, Treatment, and In-Hospital Outcomes for STEMI Patients Presenting with Non-Diagnostic Initial ECG: A Report from the AHA Mission: Lifeline Program 
American heart journal  2012;165(1):50-56.
Prior studies indicate that a subset of patients diagnosed with ST-segment elevation myocardial infarction (STEMI) will have an initial non-diagnostic ECG during evaluation. However, the timing of diagnostic ECG changes in this group is unknown. Our primary aim was to describe the timing of ECG diagnosis of STEMI in patients whose initial ECG was non-diagnostic. Secondarily, we sought to compare the delivery of ACC/AHA guidelines-based care and in-hospital outcomes in this group compared to patients diagnosed with STEMI on initial ECG.
We analyzed data from 41,560 patients diagnosed with STEMI included in the NCDR® ACTION Registry®-GWTG™ from 01/2007 to 12/2010. We divided this study population into two groups: those diagnosed on initial ECG (N= 36,994) and those with an initial non-diagnostic ECG that were diagnosed on a follow-up ECG (N= 4,566).
In general, baseline characteristics and clinical presentations were similar between the two groups. For patients with an initial non-diagnostic ECG, 72.4% (N= 3,305)had an ECG diagnostic for STEMI within 90 minutes of their initial ECG. There did not appear to be significant differences in the administration of guidelines-recommended treatments for STEMI, in-hospital major bleeding (p 0.926), or death (p 0.475) between these groups.
In a national sample of patients diagnosed with STEMI, 11.0% had an initial non-diagnostic ECG. Of those patients, 72.4% had a follow-up diagnostic ECG within 90 minutes of their initial ECG. There did not appear to be clinically meaningful differences in guidelines-based treatment or major in-hospital outcomes between patients diagnosed with STEMI on an initial versus follow-up ECG.
PMCID: PMC3523309  PMID: 23237133
9.  Associations Between NOS1AP Single Nucleotide Polymorphisms (SNPs) and QT Interval Duration in Four Racial/Ethnic Groups in the Multi-Ethnic Study of Atherosclerosis (MESA) 
QT is a risk factor for sudden cardiac death (SCD). A genome wide association study identified NOS1AP variants associated with QT, which have been replicated in predominantly Caucasian (CAU) populations. We used MESA to examine association of QT with NOS1AP variants in an ethnically diverse cohort.
Twenty-eight tagging SNPs spanning NOS1AP were genotyped in 2847 MESA participants (approximately equal numbers of CAU, African-Americans (AFA), Hispanics (HIS) and Chinese (CHN)), age 45–84 years, without cardiovascular disease. QT was measured using 12-lead ECG. Associations between QT and NOS1AP variants were evaluated using linear regression, adjusted for heart rate, age, gender, and field center stratified by ancestry, using an additive inheritance model. Ancestry informative markers (AIMs) and principal components using AIMs were used as additional covariates.
More NOS1AP SNPs were associated with QT in CAU than the other races. In CAU, each copy of rs1932933 risk allele was associated with an increase in QT (4.9msec, p= 7.20×10-7). Significant associations in CAU and HIS were located at the 5′ end, while associations in CHN were located at the 3′ end.
NOS1AP variants were associated with QT in CAU, with weaker evidence for selected variants in HIS and CHN. Location of significant SNPs varied across ancestry. We identified possible novel associations at the 3′ end of NOS1AP, where we observed significant association with QT in CHN only. Genotyping within these regions may determine functional variants affecting QT and SCD risk. Further investigations are needed across ethnically diverse population cohorts.
PMCID: PMC3642094  PMID: 23347024
Genetics; Electrocardiography; Arrhythmia; Electrophysiology
10.  Carotid Arterial Stiffness and Its Relationship to Exercise Intolerance in Older Patients with Heart Failure and Preserved Ejection Fraction 
Hypertension  2012;61(1):112-119.
Heart failure with a preserved ejection fraction (HFpEF) is the dominant form of heart failure in the older population. The primary chronic symptom in HFpEF is severe exercise intolerance, however, its pathophysiology and therapy are not well understood. We tested the hypothesis that older patients with HFpEF have increased arterial stiffness beyond that which occurs with normal aging and that this contributes to their severe exercise intolerance.
Sixty-nine patients ≥ 60 years with HFpEF and 62 healthy volunteers (24 young healthy subjects ≤ 30 years (YHC) and 38 older healthy subjects ≥ 60 years old (OHC) were examined. Carotid arterial stiffness was assessed using high-resolution ultrasound and peak exercise oxygen consumption (VO2) was measured using expired gas analysis.
Peak VO2 was severely reduced in the HFpEF patients compared to OHC (14.1±2.9 vs. 19.7±3.7 ml/kg/min; p<0.001) and in both was reduced compared to YHC subjects, (32.0±7.2 ml/kg/min; both p<0.001). In HFpEF compared to OHC, carotid arterial distensibility was reduced (0.97±0.45 vs. 1.33±0.55 × 10−3 mmHg−1, p=0.008) and Young’s elastic modulus (YEM) was increased (1320±884 vs. 925±530 kPa, p<0.02). Carotid arterial distensibility was directly (0.28; p=0.02) and YEM was inversely (−0.32; p=0.01) related with peak VO2.
Carotid arterial distensibility is decreased in HFpEF beyond the changes due to normal aging and is related to peak VO2. This supports the hypothesis that increased arterial stiffness contributes to exercise intolerance in HFpEF and is a potential therapeutic target.
PMCID: PMC3712338  PMID: 23150511
Aging; heart failure with preserved ejection fraction; arterial stiffness; exercise capacity
11.  Prognosis of Individuals with Asymptomatic Left Ventricular Systolic Dysfunction in the Multi-Ethnic Study of Atherosclerosis (MESA) 
Circulation  2012;126(23):2713-2719.
Limited data exist on the prevalence, associations and prognosis of individuals with asymptomatic left ventricular systolic dysfunction (ALVSD), especially in populations without prior clinical cardiovascular disease (CVD).
Methods and Results
Kaplan-Meier and Cox proportional hazard analyses were used to assess the association between ALVSD, defined as left ventricular ejection fraction less than 50%, and adjudicated incident congestive heart failure (CHF), all-cause mortality, and CVD events.
Out of 5004 participants, 112 participants had CHF, 321 had a CVD event, and 278 died after 9 years of follow-up. The overall prevalence of ALVSD was 1.7%, with a higher prevalence in African Americans (2.6%). ALVSD had worse cardiovascular risk profile and was also associated with increased risk in unadjusted and adjusted models for incident CHF [HR (95%): 12.0(7.04 – 20.3), p<0.0001 and 8.69(4.89 – 15.45), p<0.001 respectively], CVD [HR (95%):3.32(1.98 -5.58), p<0.001 and 2.21(1.30 – 3.73), p=0.003 respectively] and all-cause mortality [HR(95%):3.47(2.03 – 5.94), p<0.0001 and 2.00(1.13-3.54), p=0.017 respectively]. A 10% decrement in LVEF at baseline was associated with increase in risk in unadjusted and adjusted models for clinical CHF [HR (95%CI): 2.17(1.82 -2.63), p<0.0001 and 2.13(1.73 - 2.51), p<0.001 respectively] and all-cause mortality [HR (95%CI): 1.22(1.05 – 1.41), p=0.009 and 1.17(1.00 – 1.36), p=0.047 respectively]. Among the subset of participants with ALVSD, LVMI was particularly informative about risk for incident CHF (c- index = 0.74).
ALVSD is uncommon in individuals without prior clinical CVD, but is associated with high risk for CHF, CVD, and all-cause mortality. LVMI had good discrimination for incident CHF in MESA participants with ALVSD.
PMCID: PMC3533250  PMID: 23124035
heart failure; death; cardiovascular diseases; magnetic resonance imaging; population
12.  Vascular Responses to Long- and Short-Term Exposure to Fine Particulate Matter 
This study evaluated the association of long- and short-term air pollutant exposures with flow-mediated dilation (FMD) and baseline arterial diameter (BAD) of the brachial artery using ultrasound in a large multicity cohort.
Exposures to ambient air pollution, especially long-term exposure to particulate matter <2.5 μm in aerodynamic diameter (PM2.5), are linked with cardiovascular mortality. Short-term exposure to PM2.5 has been associated with decreased FMD and vasoconstriction, suggesting that adverse effects of PM2.5 may involve endothelial dysfunction. However, long-term effects of PM2.5 on endothelial dysfunction have not been investigated.
FMD and BAD were measured by brachial artery ultrasound at the initial examination of the Multi-Ethnic Study of Atherosclerosis. Long-term PM2.5 concentrations were estimated for the year 2000 at each participant’s residence (n = 3,040) using a spatio-temporal model informed by cohort-specific monitoring. Short-term PM2.5 concentrations were based on daily central-site monitoring in each of the 6 cities.
An interquartile increase in long-term PM2.5 concentration (3 μg/m3) was associated with a 0.3% decrease in FMD (95% confidence interval [CI] of difference: −0.6 to −0.03; p = 0.03), adjusting for demographic characteristics, traditional risk factors, sonographers, and 1/BAD. Women, nonsmokers, younger participants, and those with hypertension seemed to show a greater association of PM2.5 with FMD. FMD was not significantly associated with short-term variation in PM2.5 (−0.1% per 12 μg/m3 daily increase [95% CI: −0.2 to 0.04] on the day before examination).
Long-term PM2.5 exposure was significantly associated with decreased endothelial function according to brachial ultrasound results. These findings may elucidate an important pathway linking air pollution and cardiovascular mortality.
PMCID: PMC3665082  PMID: 23103035
air pollution; atherosclerosis; cardiovascular mortality; endothelial function; flow-mediated dilation; traffic
13.  Early Menopause Predicts Future Coronary Heart Disease and Stroke: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Menopause (New York, N.Y.)  2012;19(10):1081-1087.
Cardiovascular disease is the number one killer of women. Identifying women at risk of cardiovascular disease has tremendous public health importance. Early menopause is associated with increased cardiovascular disease events in some predominantly white populations, but not consistently. Our objective was to determine if a self-reported early menopause (menopause at an age <46) identifies women as at risk for future coronary heart disease or stroke.
The study population came from the Multi-Ethnic Study of Atherosclerosis, a longitudinal, ethnically diverse cohort study of US men and women aged 45 to 84 years enrolled in 2000–2002 and followed up until 2008. The association between a personal history of early menopause (either natural menopause or surgical removal of ovaries at an age <46) and future coronary heart disease and stroke was assessed in 2509 women (ages 45–84, 987 White, 331 Chinese, 641 Black, 550 Hispanic) from the Multi-Ethnic Study Atherosclerosis, who were free of cardiovascular disease at baseline.
693/2509 (28%) of women reported either surgical or natural early menopause. In survival curves, women with early menopause had worse coronary heart disease and stroke-free survival (log rank p=<0.008 and 0.0158). In models adjusted for age, race/ethnicity, Multi-Ethnic Study Atherosclerosis site and traditional cardiovascular disease risk factors, this risk for coronary heart disease and stroke remained (HR 2.08, 95% CI 1.17, 3.70 and 2.19, 95% CI 1.11, 4.32, respectively).
Early menopause is positively associated with coronary heart disease and stroke in a multiethnic cohort, independent of traditional cardiovascular disease risk factors.
PMCID: PMC3443540  PMID: 22692332
Early Menopause; Coronary Heart Disease; Stroke
15.  Relationship between genetic variants in myocardial sodium and potassium channel genes and QT interval duration in diabetics: the Diabetes Heart Study 
Genetic variants in myocardial sodium and potassium channel genes are associated with prolonged QT interval and increased risk of sudden death. It is unclear whether these genetic variants remain relevant in subjects with underlying conditions such as diabetes that are associated with prolonged QT interval.
We tested single nucleotide polymorphisms (SNPs) in five candidate genes for association with QT interval in a family-based study of subjects with type 2 diabetes mellitus (T2DM). Thirty-six previously reported SNPs were genotyped in KCNQ1, HERG, SCN5A, KCNE1, and KCNE2 in 901 European Americans from 366 families. The heart rate-corrected (QTc) durations were determined using the Marquette 12SL program. Associations between the QTc interval and the genotypes were evaluated using SOLAR adjusting for age, gender, T2DM status, and body mass index.
Within KCNQ1 there was weak evidence for association between the minor allele of IVS12+14T>C and increased QTc (p=0.02). The minor allele of rs2236609 in KCNE1 trended toward significance with longer QTc (p=0.06), while the minor allele of rs1805123 in HERG trended toward significance with shorter QTc (p=0.07). However, no statistically significant associations were observed between the remaining SNPs and QTc variation.
We found weak evidence of association between three previously-reported SNPs and QTc interval duration. While it appears as though genetic variants in previously identified candidate genes may be associated with QT duration in subjects with diabetes, the clinical implications of these associations in diabetic subjects at high risk for sudden death remains to be determined.
PMCID: PMC3650725  PMID: 19149796
QT interval; diabetes; association study; genetics; ion channels
16.  Guidelines-based treatment of anaemic STEMI patients: practice patterns and effects on in-hospital mortality: a retrospective analysis from the NCDR 
Anaemia is associated with an increased risk for morbidity and mortality in ST-elevation myocardial infarction (STEMI) patients. While several physiological mechanisms have been proposed to explain this association, decreased receipt of guidelines-based care may also contribute. We examined the relationship between admission haemoglobin (Hgb) level, receipt of ACC/AHA guidelines-based treatments, and in-hospital outcomes among STEMI patients. We also evaluated whether administration of these treatments modified the association between anaemia and in-hospital mortality in this group.
Methods and results:
We analysed data from 92,686 patients diagnosed with STEMI included in the NCDR ACTION Registry-GWTG database from January 2007 to March 2011. Patients were stratified by initial Hgb value: 83.1% (n=77,035) were classified as non-anaemic (Hgb >13.0 g/dl for men, >12.0 g/dl for women), 11.6% (n=10,710) as mildly anaemic (11.1−13.0 g/dl for men, 11.1−12.0 g/dl for women), 4.4% (n=4059) as moderately anaemic (9.1−11.0 g/dl), and 1.0% (n=882) as severely anaemic (<9.0 g/dl). Anaemia was associated with a significantly increased prevalence of other baseline comorbidities and decreased odds of receiving several class I recommended pharmacological treatments (heparin, beta-blockers, and angiotensin-converting enzyme inhibitors, p<0.01). The overall use of reperfusion therapy (fibrinolytic therapy and/or percutaneous coronary intervention) was also lower in anaemic vs. non-anaemic patients (p<0.01). Anaemia was associated higher in-hospital mortality risk, which remained significant after adjustment for use of guidelines-recommended therapies and interventions (p<0.01).
In a national sample of STEMI patients, anaemia on presentation was associated with decreased receipt of ACC/AHA guidelines-based care and higher in-hospital mortality. However, the higher mortality rates could not be fully explained by differences in in-hospital treatment.
PMCID: PMC3760583  PMID: 24062932
Anaemia; guidelines; outcomes; ST-segment myocardial infarction (STEMI); treatment
17.  Common Genetic Variation in the 3-BCL11B Gene Desert Is Associated With Carotid-Femoral Pulse Wave Velocity and Excess Cardiovascular Disease Risk The AortaGen Consortium 
Mitchell, Gary F. | Verwoert, Germaine C. | Tarasov, Kirill V. | Isaacs, Aaron | Smith, Albert V. | Yasmin | Rietzschel, Ernst R. | Tanaka, Toshiko | Liu, Yongmei | Parsa, Afshin | Najjar, Samer S. | O’Shaughnessy, Kevin M. | Sigurdsson, Sigurdur | De Buyzere, Marc L. | Larson, Martin G. | Sie, Mark P.S. | Andrews, Jeanette S. | Post, Wendy S. | Mattace-Raso, Francesco U.S. | McEniery, Carmel M. | Eiriksdottir, Gudny | Segers, Patrick | Vasan, Ramachandran S. | van Rijn, Marie Josee E. | Howard, Timothy D. | McArdle, Patrick F. | Dehghan, Abbas | Jewell, Elizabeth | Newhouse, Stephen J. | Bekaert, Sofie | Hamburg, Naomi M. | Newman, Anne B. | Hofman, Albert | Scuteri, Angelo | De Bacquer, Dirk | Ikram, Mohammad Arfan | Psaty, Bruce | Fuchsberger, Christian | Olden, Matthias | Wain, Louise V. | Elliott, Paul | Smith, Nicholas L. | Felix, Janine F. | Erdmann, Jeanette | Vita, Joseph A. | Sutton-Tyrrell, Kim | Sijbrands, Eric J.G. | Sanna, Serena | Launer, Lenore J. | De Meyer, Tim | Johnson, Andrew D. | Schut, Anna F.C. | Herrington, David M. | Rivadeneira, Fernando | Uda, Manuela | Wilkinson, Ian B. | Aspelund, Thor | Gillebert, Thierry C. | Van Bortel, Luc | Benjamin, Emelia J. | Oostra, Ben A. | Ding, Jingzhong | Gibson, Quince | Uitterlinden, André G. | Abecasis, Gonçalo R. | Cockcroft, John R. | Gudnason, Vilmundur | De Backer, Guy G. | Ferrucci, Luigi | Harris, Tamara B. | Shuldiner, Alan R. | van Duijn, Cornelia M. | Levy, Daniel | Lakatta, Edward G. | Witteman, Jacqueline C.M.
Carotid-femoral pulse wave velocity (CFPWV) is a heritable measure of aortic stiffness that is strongly associated with increased risk for major cardiovascular disease events.
Methods and Results
We conducted a meta-analysis of genome-wide association data in 9 community-based European ancestry cohorts consisting of 20,634 participants. Results were replicated in 2 additional European ancestry cohorts involving 5,306 participants. Based on a preliminary analysis of 6 cohorts, we identified a locus on chromosome 14 in the 3′-BCL11B gene desert that is associated with CFPWV (rs7152623, minor allele frequency = 0.42, beta=−0.075±0.012 SD/allele, P = 2.8 x 10−10; replication beta=−0.086±0.020 SD/allele, P = 1.4 x 10−6). Combined results for rs7152623 from 11 cohorts gave beta=−0.076±0.010 SD/allele, P=3.1x10−15. The association persisted when adjusted for mean arterial pressure (beta=−0.060±0.009 SD/allele, P = 1.0 x 10−11). Results were consistent in younger (<55 years, 6 cohorts, N=13,914, beta=−0.081±0.014 SD/allele, P = 2.3 x 10−9) and older (9 cohorts, N=12,026, beta=−0.061±0.014 SD/allele, P=9.4x10−6) participants. In separate meta-analyses, the locus was associated with increased risk for coronary artery disease (hazard ratio [HR]=1.05, confidence interval [CI]=1.02 to 1.08, P=0.0013) and heart failure (HR=1.10, CI=1.03 to 1.16, P=0.004).
Common genetic variation in a locus in the BCL11B gene desert that is thought to harbor one or more gene enhancers is associated with higher CFPWV and increased risk for cardiovascular disease. Elucidation of the role this novel locus plays in aortic stiffness may facilitate development of therapeutic interventions that limit aortic stiffening and related cardiovascular disease events.
PMCID: PMC3288392  PMID: 22068335
aorta; arterial stiffness; pulse wave velocity; genetics; cardiovascular disease
18.  Association Between Chromosome 9p21 Variants and the Ankle-Brachial Index Identified by a Meta-Analysis of 21 Genome-Wide Association Studies 
Murabito, Joanne M. | White, Charles C. | Kavousi, Maryam | Sun, Yan V. | Feitosa, Mary F. | Nambi, Vijay | Lamina, Claudia | Schillert, Arne | Coassin, Stefan | Bis, Joshua C. | Broer, Linda | Crawford, Dana C. | Franceschini, Nora | Frikke-Schmidt, Ruth | Haun, Margot | Holewijn, Suzanne | Huffman, Jennifer E. | Hwang, Shih-Jen | Kiechl, Stefan | Kollerits, Barbara | Montasser, May E. | Nolte, Ilja M. | Rudock, Megan E. | Senft, Andrea | Teumer, Alexander | van der Harst, Pim | Vitart, Veronique | Waite, Lindsay L. | Wood, Andrew R. | Wassel, Christina L. | Absher, Devin M. | Allison, Matthew A. | Amin, Najaf | Arnold, Alice | Asselbergs, Folkert W. | Aulchenko, Yurii | Bandinelli, Stefania | Barbalic, Maja | Boban, Mladen | Brown-Gentry, Kristin | Couper, David J. | Criqui, Michael H. | Dehghan, Abbas | Heijer, Martin den | Dieplinger, Benjamin | Ding, Jingzhong | Dörr, Marcus | Espinola-Klein, Christine | Felix, Stephan B. | Ferrucci, Luigi | Folsom, Aaron R. | Fraedrich, Gustav | Gibson, Quince | Goodloe, Robert | Gunjaca, Grgo | Haltmayer, Meinhard | Heiss, Gerardo | Hofman, Albert | Kieback, Arne | Kiemeney, Lambertus A. | Kolcic, Ivana | Kullo, Iftikhar J. | Kritchevsky, Stephen B. | Lackner, Karl J. | Li, Xiaohui | Lieb, Wolfgang | Lohman, Kurt | Meisinger, Christa | Melzer, David | Mohler, Emile R | Mudnic, Ivana | Mueller, Thomas | Navis, Gerjan | Oberhollenzer, Friedrich | Olin, Jeffrey W. | O’Connell, Jeff | O’Donnell, Christopher J. | Palmas, Walter | Penninx, Brenda W. | Petersmann, Astrid | Polasek, Ozren | Psaty, Bruce M. | Rantner, Barbara | Rice, Ken | Rivadeneira, Fernando | Rotter, Jerome I. | Seldenrijk, Adrie | Stadler, Marietta | Summerer, Monika | Tanaka, Toshiko | Tybjaerg-Hansen, Anne | Uitterlinden, Andre G. | van Gilst, Wiek H. | Vermeulen, Sita H. | Wild, Sarah H. | Wild, Philipp S. | Willeit, Johann | Zeller, Tanja | Zemunik, Tatijana | Zgaga, Lina | Assimes, Themistocles L. | Blankenberg, Stefan | Boerwinkle, Eric | Campbell, Harry | Cooke, John P. | de Graaf, Jacqueline | Herrington, David | Kardia, Sharon L. R. | Mitchell, Braxton D. | Murray, Anna | Münzel, Thomas | Newman, Anne | Oostra, Ben A. | Rudan, Igor | Shuldiner, Alan R. | Snieder, Harold | van Duijn, Cornelia M. | Völker, Uwe | Wright, Alan F. | Wichmann, H.-Erich | Wilson, James F. | Witteman, Jacqueline C.M. | Liu, Yongmei | Hayward, Caroline | Borecki, Ingrid B. | Ziegler, Andreas | North, Kari E. | Cupples, L. Adrienne | Kronenberg, Florian
Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts.
Methods and Results
Continuous ABI and PAD (ABI≤0.9) phenotypes adjusted for age and sex were examined. Each study conducted genotyping and imputed data to the ~2.5 million SNPs in HapMap. Linear and logistic regression models were used to test each SNP for association with ABI and PAD using additive genetic models. Study-specific data were combined using fixed-effects inverse variance weighted meta-analyses. There were a total of 41,692 participants of European ancestry (~60% women, mean ABI 1.02 to 1.19), including 3,409 participants with PAD and with GWAS data available. In the discovery meta-analysis, rs10757269 on chromosome 9 near CDKN2B had the strongest association with ABI (β= −0.006, p=2.46x10−8). We sought replication of the 6 strongest SNP associations in 5 population-based studies and 3 clinical samples (n=16,717). The association for rs10757269 strengthened in the combined discovery and replication analysis (p=2.65x10−9). No other SNP associations for ABI or PAD achieved genome-wide significance. However, two previously reported candidate genes for PAD and one SNP associated with coronary artery disease (CAD) were associated with ABI : DAB21P (rs13290547, p=3.6x10−5); CYBA (rs3794624, p=6.3x10−5); and rs1122608 (LDLR, p=0.0026).
GWAS in more than 40,000 individuals identified one genome-wide significant association on chromosome 9p21 with ABI. Two candidate genes for PAD and 1 SNP for CAD are associated with ABI.
PMCID: PMC3303225  PMID: 22199011
cohort study; genetic association; genome-wide association study; meta-analysis; peripheral vascular disease
19.  Glycemic Associations With Endothelial Function and Biomarkers Among 5 Ethnic Groups: The Multi‐Ethnic Study of Atherosclerosis and the Mediators of Atherosclerosis in South Asians Living in America Studies 
The association of prediabetic states with endothelial dysfunction measured by flow‐mediated dilation (FMD) or endothelial biomarker levels remains controversial. We examined data from 5 ethnic groups to determine the association between glucose categories and FMD or endothelial biomarkers. We determined whether these associations vary by ethnic group or body mass index.
Methods and Results
We used data from 3516 participants from 5 race/ethnic groups with brachial FMD, endothelial biomarkers, and glucose category (normal, impaired fasting glucose [IFG], and diabetes) measures. There were significant ethnic differences in FMD, biomarker levels, and the prevalence of IFG and diabetes. However, all 5 ethnic groups showed similar patterns of higher FMD for the IFG group compared with the normal glucose and diabetes groups, which was most significant among whites and Asian Indians. Associations between glucose categories and endothelial biomarkers were more uniform, with the IFG and diabetes groups having higher biomarker levels than the normal glucose group. These associations did not change with further adjustment for fasting insulin levels. Whites with normal BMI had higher FMD values with higher glucose levels, but those with BMI in the overweight or obese categories had the inverse association (P for interaction=0.01).
The discordance of IFG being associated with higher FMD but more abnormal endothelial biomarker levels is a novel finding. This higher FMD for the IFG group was most notable in whites of normal BMI. The higher FMD among those with impaired fasting glucose may reflect differences in insulin signaling pathways between the endothelium and skeletal muscle.
PMCID: PMC3603246  PMID: 23525433
biomarkers; diabetes; endothelium; ethnicity; insulin resistance
20.  Association of Pulse Pressure, Arterial Elasticity, and Endothelial Function With Kidney Function Decline Among Adults With Estimated GFR > 60 mL/min/1.73 m2: The Multi-Ethnic Study of Atherosclerosis 
The association of subclinical vascular disease and early declines in kidney function has not been well studied.
Study Design
Prospective cohort study
Setting & Participants
MESA participants with eGFR ≥60 ml/min/1.73m2 with follow-up of 5 years
Pulse pressure (pulse pressure), small and large arterial elasticity (SAE, LAE), and flow mediated dilation.
kidney function decline
SAE and LAE were measured by pulse contour analysis of the radial artery. Kidney function was measured by serum creatinine- and cystatin C-based eGFR.
Among 4,853 adults, higher pulse pressure and lower SAE and LAE had independent and linear associations with faster rates of kidney function decline. Compared to persons with pulse pressure 40–50mmHg, eGFRSCysC decline was 0.29 (p=0.006), 0.56 (p<0.001), and 0.91 (p<0.001) ml/min/1.73m2/year faster among persons with pulse pressure 50–60, 60–70, and >70mmHg, respectively. Compared to the highest quartile of SAE (most elastic), eGFRSCysC decline was 0.26 (p=0.009), 0.35 (p=0.001), and 0.70 (p<0.001) ml/min/1.73m2/year faster for the second, third and fourth quartiles respectively. For LAE, compared to the highest quartile, eGFRSCysC decline was 0.28 (p=0.004), 0.58 (p<0.001), and 0.83 (p<0.001) ml/min/1.73m2/year faster for each decreasing quartile of LAE. Findings were similar with creatinine-based eGFR. In contrast, among 2,997 adults with flow-mediated dilation and kidney function measures, flow-mediated dilation was not significantly associated with kidney function decline. For every 1-SD greater flow-mediated dilation, eGFRSCysC and eGFRSCr changed by 0.05 ml/min/1.73m2/year (p=0.3) and 0.06 ml/min/1.73m2/year (p=0.04), respectively.
We had no direct measure of GFR, in common with nearly all large population based studies.
Higher pulse pressure and lower arterial elasticity, but not flow-mediated dilation, were linearly and independently associated with faster kidney function decline among persons with eGFR ≥60 ml/min/1.73m2. Future studies investigate whether treatments to lower stiffness of large and small arteries may slow the rate of kidney function loss.
PMCID: PMC3242889  PMID: 22000727
kidney function; arterial elasticity; chronic kidney disease; atherosclerosis
21.  An Overview of Population Genetic Data Simulation 
Simulation studies in population genetics play an important role in helping to better understand the impact of various evolutionary and demographic scenarios on sequence variation and sequence patterns, and they also permit investigators to better assess and design analytical methods in the study of disease-associated genetic factors. To facilitate these studies, it is imperative to develop simulators with the capability to accurately generate complex genomic data under various genetic models. Currently, a number of efficient simulation software packages for large-scale genomic data are available, and new simulation programs with more sophisticated capabilities and features continue to emerge. In this article, we review the three basic simulation frameworks—coalescent, forward, and resampling—and some of the existing simulators that fall under these frameworks, comparing them with respect to their evolutionary and demographic scenarios, their computational complexity, and their specific applications. Additionally, we address some limitations in current simulation algorithms and discuss future challenges in the development of more powerful simulation tools.
PMCID: PMC3244809  PMID: 22149682
backward simulators; disease association study; forward simulators; genome simulation; resampling
22.  Genome-wide Association Study for Coronary Artery Calcification with Follow-up in Myocardial Infarction 
Circulation  2011;124(25):2855-2864.
Coronary artery calcification (CAC) detected by computed tomography is a non-invasive measure of coronary atherosclerosis, that underlies most cases of myocardial infarction (MI). We aimed to identify common genetic variants associated with CAC and further investigate their associations with MI.
Methods and Results
Computed tomography was used to assess quantity of CAC. A meta-analysis of genome-wide association studies for CAC was carried out in 9,961 men and women from five independent community-based cohorts, with replication in three additional independent cohorts (n=6,032). We examined the top single nucleotide polymorphisms (SNPs) associated with CAC quantity for association with MI in multiple large genome-wide association studies of MI. Genome-wide significant associations with CAC for SNPs on chromosome 9p21 near CDKN2A and CDKN2B (top SNP: rs1333049, P=7.58×10−19) and 6p24 (top SNP: rs9349379, within the PHACTR1 gene, P=2.65×10−11) replicated for CAC and for MI. Additionally, there is evidence for concordance of SNP associations with both CAC and with MI at a number of other loci, including 3q22 (MRAS gene), 13q34 (COL4A1/COL4A2 genes), and 1p13 (SORT1 gene).
SNPs in the 9p21 and PHACTR1 gene loci were strongly associated with CAC and MI, and there are suggestive associations with both CAC and MI of SNPs in additional loci. Multiple genetic loci are associated with development of both underlying coronary atherosclerosis and clinical events.
PMCID: PMC3397173  PMID: 22144573
cardiac computed tomography; coronary artery calcification; coronary atherosclerosis; genome-wide association studies; myocardial infarction
23.  Association Between Sleep Apnea, Snoring, Incident Cardiovascular Events and All-Cause Mortality in an Adult Population. MESA 
Atherosclerosis  2011;219(2):963-968.
We assessed the association between sleep apnea, snoring, incident cardiovascular (CV) events and all-cause mortality in the Multi Ethnic Study of Atherosclerosis (MESA) cohort.
Out of 5338 respondents to a sleep questionnaire administered during the second MESA exam period, 208 had physician-diagnosed sleep apnea (PDSA), 1452 were habitual snorers (HS) and 3678 were neither a habitual snorer nor had PDSA (normal participants). Cox proportional hazard analysis was used to assess the associations adjusting for age, gender, race/ethnicity, smoking, diabetes mellitus, total cholesterol, HDL, triglycerides, BMI, current alcohol use, benzodiazepine use, BP medications and statin use.
Over a 7.5 year average follow-up period, 310 adjudicated CV events including MI, stroke, angina, resuscitated cardiac arrest, stroke death and CVD death and 189 deaths occurred. Compared to HS, PDSA was associated with higher incident CV rates in both univariate and multivariable models [hazard ratio (95%); 1.89(1.22–2.93), p=0.004 and 1.91(1.20 –3.04), p=0.007 respectively]. PDSA was also associated with a higher death rates compared with HS [hazard ratio (95%); 2.13(1.25 – 3.63), p=0.006 and 2.70(1.52– 4.79), p=0.007 respectively]. Compared with normal participants, PDSA had higher incident CV event rates in both univariate and multivariable models [hazard ratio (95%); 2.23[1.39–3.60], p=0.001 and 2.16[1.30–3.58], p=0.003 respectively]. Similarly, PDSA had a higher death rate compared with normal participants in both the univariate and multivariable models [hazard ratio (95%CI); 2.44(1.36 – 4.37), p=0.003 and 2.71(1.45 – 5.08), p=0.002 respectively]. Habitual snorers had similar incident CV event rates and death rates in both univariate and multivariable models compared with normal participants.
PDSA but not habitual snoring was associated with high incident CV events and all-cause mortality in a multi-ethnic population based study of adults free of clinical CV disease at baseline.
PMCID: PMC3255297  PMID: 22078131
Obstructive sleep apnea; habitual snorers; cardiovascular events; mortality; population
24.  Modification of the Effect of Glycemic Status on Aortic Distensibility by Age in the Multi-Ethnic Study of Atherosclerosis 
Hypertension  2009;55(1):26-32.
Elevated serum glucose from diabetes mellitus (DM) or impaired fasting glucose (IFG) shares many mechanisms with aging that decrease aortic distensibility (AD), such as glycation of the extra-cellular matrix. However, little data compares the simultaneous effects of elevated serum glucose and aging on AD. To study this, we examined the relationship between fasting glucose status, age, and AD in the Multi-Ethnic Study of Atherosclerosis (MESA): a multi-ethnic cohort of individuals aged 45-84 years without clinical cardiovascular disease. In MESA, participants with normal fasting glucose (NFG; n = 2270), IFG (n = 870), and DM (n = 412) underwent MRI assessment of proximal thoracic aortic distensibility. This sample was 46% male, 42% white, 30% AA, 11% Asian, and 17% Hispanic. The relationship between glucose status, age, and AD was analyzed with general linear models by adjusting for factors influential on AD. An interaction term was used to determine if age modified the effect of glucose status on AD. AD was lowest among those with DM. The interaction term was significant (p = 0.024). Comparing participants less than 65 years of age, AD was different between NFG and DM (p < 0.01), and between NFG and IFG (p = 0.02). In those older than 65, fasting glucose group was no longer a significant predictor of AD. Our data indicate that there are overall differences in AD between DM, IFG, and NFG. However, age modified the effect of glucose status such that differences between the groups diminished with advancing age.
PMCID: PMC3400507  PMID: 19933927
aging; aorta; diabetes mellitus; glucose; magnetic resonance imaging
25.  Impaired Fasting Glucose And The Risk Of Incident Diabetes Mellitus And Cardiovascular Events In An Adult Population: The Multi-Ethnic Study of Atherosclerosis 
To assess the cardiovascular risk of impaired fasting glucose (IFG).
The association between IFG, incident type 2 diabetes mellitus (T2DM) and cardiovascular (CV) events remains unclear.
The Multi-Ethnic Study of Atherosclerosis (MESA) included participants aged 45–84 free of clinical CV disease at baseline (2000–2002). T2DM was defined as fasting glucose >125mg/dl or anti-diabetes medication at baseline and follow-up exams, IFG as no T2DM and fasting glucose 100– Cox proportional hazard analysis was used to assess the association between IFG and incident DM and also with incident CV events.
Of 6753 participants included in these analyses 840 (12.7%) had T2DM, 940 (13.8%) had IFG at the baseline exam. During 7.5 years of follow-up there were 418 adjudicated CV events. T2DM was associated with an increased CV incidence in the univariate [hazard ratio (HR); 2.83(2.25–3.56), p<0.0001] and multivariable models (adjusted for demographics and traditional risk factors) [HR; 1.87(1.47 – 2.37), p<0.0001] compared with subjects without T2DM (IFG + NFG). IFG was associated with increased incidence of T2DM [HR; 13.2 (95%CI 10.8–16.2), p<0.001] that remained after adjusting for demographics, highest educational level, physical activity and BMI [HR; 10.5(8.4–13.1), p<0.001] compared to NFG. IFG was associated with incident CV events in the univariate [HR; 1.64(1.26 – 2.14), p=<0.001] but not in the full multivariable model [HR; 1.16(95% CI 0.88–1.52), p=0.3] compared with NFG.
Having IFG was not independently associated with an increased short-term risk for incident CV events. These data reiterate the importance of intervention in persons with IFG to reduce their incidence of T2DM.
PMCID: PMC3146297  PMID: 21718910
Impaired fasting glucose; diabetes mellitus; cardiovascular events; population

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