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1.  Assessing the Utility of Methods for Menopausal Transition Classification in a Population-Based Cohort: The CARDIA Study 
Maturitas  2013;75(3):289-293.
Perimenopause significantly impacts women’s health, but is under-researched due to challenges in assessing perimenopause status. Using CARDIA data, we compared the validity of six approaches for classifying perimenopause status in order to better understand the performance of classification techniques which can be applied to general cohort data. Specifically, we examined the validity of a self-reported question concerning changes in menstrual cycle length and two full prediction models using all available data concerning menstrual cycles as potential indicators of perimenopause. The validity of these three novel methods of perimenopause classification were compared to three previously established classification methods.
For each method, women were classified as pre- or peri-menopausal at Year 15 of follow-up (ages 32–46). Year 15 perimenopause status was then used to predict Year 20 post-menopausal status (yes/no) to estimate measures of validity and area under the curve.
The validity of the methods varied greatly, with four having an area under the curve greater than 0.8.
When designing studies, researchers should collect the data required to construct a prediction model for classifying perimenopause status that includes age, smoking status, vasomotor symptoms, and cycle irregularities as predictors. The inclusion of additional data regarding menstrual cycles can be used to construct a full prediction model which may offer improved validity. Valid classification methods that use readily available data are needed to improve the scientific accuracy of research regarding perimenopause, promote research on this topic, and inform clinical practices.
PMCID: PMC3767146  PMID: 23707105
menopause; perimenopause; sensitivity; specificity; validity
2.  Association of Electrocardiographically Determined Left Ventricular Mass With Incident Diabetes, 1985–1986 to 2010–2011 
Diabetes Care  2013;36(3):645-647.
Electrocardiographic indices reflecting left ventricular hypertrophy are associated with incident diabetes in clinical populations at risk for coronary heart disease. We tested whether electrocardiographically determined left ventricular mass was positively associated with incident diabetes in a population sample.
Coronary Artery Risk Development in Young Adults (CARDIA) study participants (n = 4,739) were followed from 1985–1986 to 2010–2011 for incident diabetes. Validated sex- and race-specific formulas were applied to standard electrocardiograms to determine left ventricular mass.
Over 25 years, 444 participants developed diabetes (9.4%). After adjustment for demographic, behavioral, and clinical covariates, participants in the highest quartile of left ventricular mass index (LVMI) were twice as likely to develop diabetes than participants in the lower three quartiles (hazard ratio 2.61 [95% CI 2.16–3.17]). Neither Cornell voltage nor Cornell voltage product was associated with incident diabetes in fully adjusted models.
Electrocardiographically determined LVMI may be a useful noninvasive marker for identifying adults at risk for diabetes.
PMCID: PMC3579342  PMID: 23160723
3.  Passive Smoke Exposure Trends and Workplace Policy in the Coronary Artery Risk Development in Young Adults (CARDIA) study (1985–2001) 
Preventive medicine  2007;44(6):490-495.
There has been reduced active smoking, decreased societal acceptance for smoking indoors, and changing smoking policy since the mid-1980s. We quantified passive smoke exposure trends and their relationship with workplace policy.
We studied 2,504 CARDIA participants (blacks and whites, 18–30 years old when recruited in 1985–86 from four US cities, reexamination 2, 5, 7, 10, and 15 years later) who never reported smoking and attended exams at 10 or 15 years.
In non-smokers with a college degree (n = 1,581), total passive smoke exposure declined from 16.3 hr/wk in 1985/86 to 2.3 hr/wk in 2000/01. Less education tended to be associated with more exposure at all timepoints for example, in high school or less (n = 349) 22.2 hours/wk in 1985/86 to 8.5 hr/wk in 2000/01. Those who experienced an increase in the restrictiveness of self-reported workplace smoking policy from 1995/96 to 2000/01 were exposed to almost 3 hours per week less passive smoke than those whose workplace policies became less restrictive in this time period.
The increasing presence of restrictive workplace policies seemed to be a component of the substantial decline in self-reported passive smoke exposure since 1985.
PMCID: PMC3902070  PMID: 17433426
Environmental Tobacco Smoke Pollution; Occupational Health; Passive Smoking; Socioeconomic factors
4.  Maintaining a High Physical Activity Level Over 20 Years and Weight Gain 
JAMA : the journal of the American Medical Association  2010;304(23):10.1001/jama.2010.1843.
Data supporting physical activity guidelines to prevent long-term weight gain are sparse, particularly during the period when the highest risk of weight gain occurs.
To evaluate the relationship between habitual activity levels and changes in body mass index (BMI) and waist circumference over 20 years.
Design, Setting, and Participants
The Coronary Artery Risk Development in Young Adults (CARDIA) study is a prospective longitudinal study with 20 years of follow-up, 1985-86 to 2005-06. Habitual activity was defined as maintaining high, moderate, and low activity levels based on sex-specific tertiles of activity scores at baseline. Participants comprised a population-based multi-center cohort (Chicago, Illinois; Birmingham, Alabama; Minneapolis, Minnesota; and Oakland, California) of 3554 men and women aged 18 to 30 years at baseline.
Main Outcome Measures
Average annual changes in BMI and waist circumference
Over 20 years, maintaining high levels of activity was associated with smaller gains in BMI and waist circumference compared with low activity levels after adjustment for race, baseline BMI, age, education, cigarette smoking status, alcohol use, and energy intake. Men maintaining high activity gained 2.6 fewer kilograms (+ 0.15 BMI units per year; 95 % confidence interval [CI] 0.11-0.18 vs +0.20 in the lower activity group; 95% CI, 0.17-0.23) and women maintaining higher activity gained 6.1 fewer kilograms (+0.17 BMI units per year; 95 % CI, 0.12-0.21 vs. +0.30 in the lower activity group; 95 % CI, 0.25-0.34). Men maintaining high activity gained 3.1 fewer centimeters in waist circumference (+0.52 cm per year; 95 % CI, 0.43-0.61 cm vs 0.67 cm in the lower activity group; 95 % CI, 0.60-0.75) and women maintaining higher activity gained 3.8 fewer centimeters (+0.49 cm per year; 95 % CI, 0.39-0.58 vs 0.67 cm in the lower activity group; 95 % CI, 0.60-0.75).
Maintaining high activity levels through young adulthood may lessen weight gain as young adults transition to middle age, particularly in women.
PMCID: PMC3864556  PMID: 21156948
5.  Correlates of heart rate recovery over 20 years in a population sample 
Medicine and science in sports and exercise  2012;44(2):10.1249/MSS.0b013e31822cb190.
Slow heart rate recovery (HRR) from a graded exercise treadmill test (GXT) is a marker of impaired parasympathetic reactivation that is associated with elevated mortality. Our objective was to test whether demographic, behavioral or coronary heart disease (CHD) risk factors during young adulthood were associated with the development of slow HRR.
Participants from the Coronary Artery Risk Development in Young Adults study underwent symptom-limited maximal GXT using a modified Balke protocol at baseline (1985–86) and 20-year follow-up (2005–06) examinations. HRR was calculated as the difference between peak heart rate (HR) and HR two-minutes following cessation of the GXT. Slow HRR was defined as 2-minute HRR < 22 beats·min−1.
In 2,730 participants who did not have slow HRR at baseline, mean HRR was 44 beats*min−1 (SD = 11) at baseline and declined to 40 beats·min−1 (SD=12) in 2005–06; slow HRR developed in 5% (n=135) of the sample by 2005–06. Female sex, black race, fewer years of education, obesity, cigarette smoking, higher depressive symptoms, higher fasting glucose, hypertension, metabolic syndrome and physical inactivity and low fitness were each associated with incident slow HRR. In a multivariable model higher BMI, larger waist, low education, fasting glucose and current smoking remained significantly associated with incident slow HRR. Increasing BMI (per SD higher) over follow-up and incident hypertension, diabetes and metabolic syndrome (in the subsets of participants who were free from those conditions at baseline), were each associated with a significantly elevated odds of incident slow HRR.
On average, HRR declines with aging; however, the odds of having slow HRR in early middle age is significantly associated with traditional CHD risk factors.
PMCID: PMC3838873  PMID: 21796053
Epidemiology; Cardiovascular Disease; Exercise; Autonomic Nervous System
6.  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
7.  Black–White Differences in Hysterectomy Prevalence: The CARDIA Study 
American journal of public health  2008;99(2):300-307.
We evaluated the cross-sectional association between race and hysterectomy prevalence in a population-based cohort of US women and investigated participant characteristics associated with racial differences.
The cohort consisted of 1863 Black and White women in the Coronary Artery Risk Development in Young Adults (CARDIA) study from 2000 to 2002 (years 15 and 16 after baseline). We used logistic regression to examine unadjusted and multivariable adjusted odds ratios.
Black women demonstrated greater odds of hysterectomy compared with White women (odds ratio [OR]=3.52; 95% confidence interval [CI]=2.52, 4.90). Adjustment for age, educational attainment, perceived barriers to accessing medical care, body mass index, polycystic ovarian syndrome, tubal ligation, depressive symptoms, age at menarche, and geographic location minimally altered the association (OR=3.70; 95% CI=2.44, 5.61). In a subset of the study population, those with directly imaged fibroids, the association was minimally attenuated (OR=3.47; 95% CI=2.23, 5.40).
In both unadjusted and multivariable adjusted models, Black women, compared with White women, had increased odds of hysterectomy that persisted despite adjustment for participant characteristics. The increased odds are possibly related to decisions to undergo hysterectomy.
PMCID: PMC2622766  PMID: 19059854
8.  Association of Sex Hormones and SHBG with Depressive Symptoms in Post-menopausal Women: the Multi-Ethnic Study of Atherosclerosis 
Menopause (New York, N.y.)  2012;19(8):877-885.
Sex hormones are thought to play an important role in the pathophysiology of depressive disorders in women. This study assessed the associations of total testosterone (T), bioavailable T, estradiol (E2), dehydroepiandrosterone (DHEA) and sex hormone binding globulin (SHBG) with depressive symptoms stratified on postmenopausal stage to determine whether associations were strongest for early postmenopausal women.
Women (N=1824) free of depressive symptoms at baseline (2000–2002) in the Multi-Ethnic Study of Atherosclerosis were categorized into tertiles of years postmenopause: T1, 0–10 years; T2, 11–20 years; and T3, 21–58 years. Multivariable-adjusted relative risks (RR) and 95% confidence intervals were computed for the incidence of depressive symptoms, as defined by a score of 16 or higher on the Center for Epidemiologic Studies Depression scale at examination 3 (2004–2005).
In analysis including all sex hormones, the RRs for incident depressive symptoms associated with 1 unit higher log(total T) was 0.57 (p=0.13), log(E2) was 0.78 (p=0.04), log(SHBG) was 1.84 (p=0.003) and log(DHEA) was 1.45 (p=0.08) in T1. Without adjustment for SHBG, the RR for log(bioavailable T) was 0.16 (p=0.04). However, in T2 and T3, there were no meaningful associations of hormone or SHBG levels with incident depressive symptoms. When stratified by HT use, results were consistent for HT users but attenuated for HT non-users.
In women early postmenopause, sex hormones were associated with incident depressive symptoms.
PMCID: PMC3376685  PMID: 22415566
sex hormones; CES-D; depression; testosterone; estradiol; SHBG
9.  Polygenic Association with Total Homocysteine in the Post Folic Acid Fortification Era: the CARDIA Study 
Molecular genetics and metabolism  2009;98(1-2):181-186.
Elevated plasma concentration of total homocysteine (tHcy) has been linked with many diseases. tHcy is associated with a variety of factors, including polymorphisms in genes involved in homocysteine metabolism. It is not clear whether US-mandated fortification of grain products with folic acid has affected the association of genetic variants with tHcy levels. We determined tHcy concentrations in sera from 997 Caucasians and 692 African Americans participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study before and after folic acid fortification. DNA was genotyped for variants present in four genes involved in homocysteine metabolism: cystathionine β-synthase (CBS) 844ins68, methionine synthase (MS) 2756A>G; methionine synthase reductase (MTRR) 66A>G, and methylenetetrahydrofolate reductase (MTHFR) 677C>T and 1298A>C. A greater number of African Americans were homozygous for the MS 2756GG, MTRR 66GG and CBS 844ins68 genotypes compared to Caucasians, while prevalence of MTHFR 677TT and 1298CC genotypes was substantially lower in African Americans compared to Caucasians. The overall variance in tHcy levels at y 0, 7, and 15 that can be explained by the combined presence of all five variants increased slightly over time in Caucasians (17%, y 0; 21%, y 7 and 26%, y 15) and in African Americans (13%, y 0; 17% y 7; 18% y 15) largely due to decrease in tHcy variance.
PMCID: PMC3578421  PMID: 19577940
Cystathionine B-synthase; folic acid; homocysteine; methylenetetrahydrofolate reductase; methionine synthase; methionine synthase reductase
10.  Prevalence of Electrocardiographic Abnormalities in a Middle-Aged, Biracial Population: Coronary Artery Risk Development in Young Adults (CARDIA) Study 
Journal of electrocardiology  2010;43(5):385.e1-385.e9.
Few studies to date have described the prevalence of electrocardiographic (ECG) abnormalities in a biracial middle-aged cohort.
Methods and Results
Participants underwent measurement of traditional risk factors and 12-lead ECGs coded using both Minnesota Code (MC) and Novacode (NC) criteria. Among 2585 participants, of whom 57% were women and 44% were black (mean age 45 years), the prevalence of major and minor abnormalities were significantly higher (all P<0.001) among black men and women compared to whites. These differences were primarily due to higher QRS voltage and ST/T wave abnormalities among blacks. There was also a higher prevalence of Q waves (MC 1-1, 1-2, 1-3) than described by previous studies. These racial differences remained after multivariate adjustment for traditional cardiovascular (CV) risk factors.
Black men and women have a significantly higher prevalence of ECG abnormalities, independent of traditional CV risk factors, than whites in a contemporary cohort middle-aged participants.
PMCID: PMC3569004  PMID: 20374967
11.  Comparison of the Racial/Ethnic Prevalence of Regular Aspirin Use for the Primary Prevention of Coronary Heart Disease from the Multi-Ethnic Study of Atherosclerosis 
In 2002 the United States Preventive Services Task Force and the American Heart Association recommended aspirin for the primary prevention of Coronary Heart Disease (CHD) in individuals with a Framingham risk score ≥ 6% or ≥ 10%, respectively. The regular use of aspirin (≥ 3 days per week) was examined in a cohort of 6452 White, Black, Hispanic, and Chinese individuals without cardiovascular disease in 2000-2002 and 5181 individuals from the same cohort in 2005-2007. Framingham risk scores were stratified into low (< 6%), increased (6% to 9.9%), and high risk (≥ 10%). In 2000-2002 the prevalence of aspirin use was 18% and 27% for those at increased and high risk, respectively. Whites (25%) used aspirin more than Blacks (14%), Hispanics (12%), or Chinese (14%) (P < 0.001) in the increased risk group. Corresponding prevalences for the high risk group were 38%, 25%, 17%, and 21%, respectively (P < 0.001). In 2005-2007 the prevalence of aspirin use was 31% and 44% for those at increased and high risk, respectively. Whites (41%) used aspirin more than Blacks (27%), Hispanics (24%), or Chinese (15%) in the increased risk group (P < 0.001). Corresponding prevalences for the high risk group were 53%, 43%, 38%, and 28%, respectively (P < 0.001). Racial/ethnic differences persisted after adjustment for age, gender, diabetes, income, and education. In conclusion, regular aspirin use in adults at increased and high risk for CHD remains suboptimal. Important racial/ethnic disparities exist for unclear reasons.
PMCID: PMC3021117  PMID: 21146684
Framingham risk score; aspirin; coronary heart disease; race and ethnicity
12.  Lower Extremity Fat Mass Is Associated With Insulin Resistance in Overweight and Obese Individuals: The CARDIA Study 
Obesity (Silver Spring, Md.)  2011;19(11):2248-2253.
Lower extremity fat mass (LEFM) has been shown to be favorably associated with glucose metabolism. However, it is not clear whether this relationship is similar across varying levels of obesity. We hypothesized that lower amounts of LEFM is associated with higher insulin resistance (IR) and this association may vary according to weight status. Participants with available measures were examined from the Coronary Artery Risk Development in Young Adults study (CARDIA), a multi-center longitudinal study of the etiology of atherosclerosis in black and white men and women aged 38–50 years old in 2005–2006 (n = 1,579). The homeostasis model assessment of IR (HOMAIR) was calculated to estimate IR, regional adiposity was measured using dual energy X-ray absorptiometry (DXA), and weight status was defined according to BMI categories. Obese and overweight participants exhibited higher IR, total fat mass (FM), trunk FM (TFM), and LEFM compared to normal weight participants. After controlling for age, height, race, study center, education, smoking, and cardiorespiratory fitness (CRF), greater LEFM was significantly associated with higher IR only in normal weight men and women. Further adjustment for TFM revealed that lower LEFM was significantly associated with higher IR in overweight and obese men and women and the positive association in normal weight individuals was attenuated. These results suggest that excess adiposity in the lower extremities may attenuate the metabolic risk observed at a given level of abdominal adiposity in overweight and obese individuals. Weight status presents additional complexity since the metabolic influence of adipose tissue may not be homogenous across anatomic regions or level of obesity.
PMCID: PMC3203327  PMID: 21617639
13.  Longitudinal Examination of Age-Predicted Symptom-Limited Exercise Maximum Heart Rate 
To estimate the association of age with maximal heart rate (MHR).
Data were obtained in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Participants were black and white men and women aged 18-30 in 1985-86 (year 0). A symptom-limited maximal graded exercise test was completed at years 0, 7, and 20 by 4969, 2583, and 2870 participants, respectively. After exclusion 9622 eligible tests remained.
In all 9622 tests, estimated MHR (eMHR, beats/minute) had a quadratic relation to age in the age range 18 to 50 years, eMHR=179+0.29*age-0.011*age2. The age-MHR association was approximately linear in the restricted age ranges of consecutive tests. In 2215 people who completed both year 0 and 7 tests (age range 18 to 37), eMHR=189–0.35*age; and in 1574 people who completed both year 7 and 20 tests (age range 25 to 50), eMHR=199–0.63*age. In the lowest baseline BMI quartile, the rate of decline was 0.20 beats/minute/year between years 0-7 and 0.51 beats/minute/year between years 7-20; while in the highest baseline BMI quartile there was a linear rate of decline of approximately 0.7 beats/minute/year over the full age of 18 to 50 years.
Clinicians making exercise prescriptions should be aware that the loss of symptom-limited MHR is much slower at young adulthood and more pronounced in later adulthood. In particular, MHR loss is very slow in those with lowest BMI below age 40.
PMCID: PMC2891874  PMID: 20639723
prediction equations; graded exercise test; mixed models; epidemiologic study
14.  Joint Associations of Physical Activity and Aerobic Fitness on the Development of Incident Hypertension: Coronary Artery Risk Development in Young Adults (CARDIA) 
Hypertension  2010;56(1):49-55.
Fitness and physical activity are each inversely associated with the development of hypertension. We tested whether fitness and physical activity were independently associated with the 20-year incidence of hypertension in 4618 men and women. Hypertension was determined in participants who had systolic blood pressure (SBP)≥140 mmHg or diastolic blood pressure (DBP) ≥90 mmHg or who reported antihypertensive medication use. Fitness was estimated based on the duration of a symptom-limited graded exercise treadmill test and physical activity was self-reported. The incidence rate of hypertension was 13.8 per 1000 person-years (n=1022). Both baseline fitness (hazard ratio [HR]=0.63, 95% confidence interval [CI]: 0.56, 0.70 per standard deviation [SD; 2.9 minutes]) and physical activity (HR=0.86, 95% CI: 0.79, 0.84 per SD [297 exercise units]) were inversely associated with incident hypertension when included jointly in a model that also adjusted for age, sex, race, baseline smoking status, SBP, alcohol intake, HDL cholesterol, dietary fiber, dietary sodium, fasting glucose and BMI. The magnitude of association between physical activity and hypertension was strongest among participants in the high fitness (HR= 0.80, 95% CI: 0.68, 0.94) category, whereas the magnitude of association between fitness and hypertension was similar across tertiles of physical activity. The estimated proportion of hypertension cases that could be prevented if participants moved to a higher fitness category (i.e., preventive fraction) was 34% and varied by race and sex group. Fitness and physical activity are each associated with incident hypertension, and low fitness may account for a substantial proportion of hypertension incidence.
PMCID: PMC2909350  PMID: 20516395
epidemiology; exercise; ethnicity; risk factors; special populations
15.  Passive Smoke Exposure and Circulating Carotenoids in the CARDIA Study 
Annals of Nutrition & Metabolism  2010;56(2):113-118.
Our objective was to assess associations between passive smoke exposure in various venues and serum carotenoid concentrations.
CARDIA is an ongoing longitudinal study of the risk factors for subclinical and clinical cardiovascular disease. At baseline in 1985/1986, serum carotenoids were assayed and passive smoke exposure inside and outside of the home and diet were assessed by self-report. Our analytic sample consisted of 2,633 black and white non-smoking adults aged 18–30 years.
Greater total passive smoke exposure was associated with lower levels of the sum of the three provitamin A carotenoids, α-carotene, β-carotene, and β-cryptoxanthin (–0.048 nmol/l per hour of passive smoke exposure, p = 0.001), unassociated with lutein/zeaxanthin, and associated with higher levels of lycopene (0.027 nmol/l per hour of passive smoke exposure, p = 0.010) after adjustment for demographics, diet, lipid profile, and supplement use. Exposure in both home and non-home spaces was also associated with lower levels of the provitamin A carotenoid index.
Cross-sectionally, in 1985/86, passive smoke exposure in various venues was associated with reduced levels of provitamin A serum carotenoids.
PMCID: PMC2842165  PMID: 20110671
Carotenoids; Micronutrients; Occupational health; Passive smoking; Smoke exposure; Tobacco smoke pollution
16.  Associations of Lipoprotein Lipase Gene Polymorphisms with Longitudinal Plasma Lipid Trends in Young Adults: the CARDIA Study 
Genome-wide association studies (GWAS) in European Americans have reported several SNPs in the lipoprotein lipase (LPL) gene associated with plasma levels of HDL-C and triglycerides. However, the influences of the LPL SNPs on longitudinal changes of these lipids have not been systematically examined.
Methods and Results
Based on data from 2045 African American and 2116 European American young adults in the CARDIA Study, we investigated cross-sectional and longitudinal associations of lipids with 8 LPL SNPs, including two that have been reported in GWAS. Plasma levels of HDL-C and triglycerides were measured at seven examinations during 20 years of follow-up. In European Americans, rs328 (Ser447Stop), rs326 and rs13702 were significantly associated with cross-sectional interindividual variations in triglycerides and HDL-C (p<0.005) and with their longitudinal changes over time (p < 0.05). The minor alleles in rs326, rs328, and rs13702 that predispose an individual to lower triglycerides and higher HDL-C levels at young adulthood further slow down the trajectory increase in triglycerides and decrease in HDL-C during 20 years of follow-up. In African Americans, these 3 SNPs were significantly associated with triglycerides but only rs326 and rs13702 associated with HDL-C (p<0.008). Rs328 showed a stronger association in European Americans than African Americans and adjustment for it did not remove all of the associations for the other SNPs. Longitudinal changes in either trait did not differ significantly by SNP genotypes in African Americans.
Our data suggest that aging interacts with LPL gene variants to influence the longitudinal lipid variations and there is population-related heterogeneity in the longitudinal associations.
PMCID: PMC3004750  PMID: 20150529
lipids; genetics; epidemiology; LPL gene
17.  Ala54Thr polymorphism of the fatty acid binding protein 2 gene and saturated fat intake in relation to lipid levels and insulin resistance: The Coronary Artery Risk Development in Young Adults (CARDIA) Study 
The Thr54 allele of the intestinal fatty acid-binding protein Ala54Thr functional polymorphism (FABP2) is associated with increased fat oxidation and insulin resistance. We determined the cross-sectional associations of the FABP2 gene with lipid levels and insulin resistance in 2148 participants who completed the year 20 exam of the Coronary Artery Risk Development in Young Adults (CARDIA) study. No significant difference in total cholesterol, low-density or high-density lipoprotein cholesterol, triglycerides, high-density lipoprotein cholesterol to total cholesterol ratio, or HOMA-IR was found between FABP2 genotypes. However, in the presence of a high saturated fat diet (≥ 53.2 grams per day, the 90th percentile for the population), the AA/AG genotypes (carriers of the Thr54 allele) of FABP2 had statistically significantly higher levels of log(HOMA-IR) (p=0.006) and a lower high-density lipoprotein cholesterol to total cholesterol ratio (p=0.03), and borderline statistically significantly higher levels of total cholesterol, low-density lipoprotein cholesterol, and log(triglycerides) (p-values = 0.08, 0.07, and 0.05, respectively) compared to those with the GG genotype (Ala54 homozygotes). Lipid levels and log(HOMA-IR) did not vary by genotype with saturated fat intake below 53.2 grams per day. Limiting dietary saturated fat intake may be particularly important among carriers of the A allele of FABP2.
PMCID: PMC2728792  PMID: 19439328
intestinal fatty acid-binding protein; FABP2; lipids; insulin resistance; saturated fat
18.  Association of 20-Year Changes in Cardiorespiratory Fitness With Incident Type 2 Diabetes 
Diabetes Care  2009;32(7):1284-1288.
To test the association of fitness changes over 7 and 20 years on the development of diabetes in middle age.
Fitness was determined based on the duration of a maximal graded exercise treadmill test (Balke protocol) at up to three examinations over 20 years from 3,989 black and white men and women from the Coronary Artery Risk Development in Young Adults study. Relative fitness change (percent) was calculated as the difference between baseline and follow-up treadmill duration/baseline treadmill duration. Diabetes was identified as fasting glucose ≥126 mg/dl, postload glucose ≥200 mg/dl, or use of diabetes medications.
Diabetes developed at a rate of 4 per 1,000 person-years in women (n = 149) and men (n = 122), and lower baseline fitness was associated with a higher incidence of diabetes in all race-sex groups (hazard ratios [HRs] from 1.8 to 2.3). On average, fitness declined 7.6% in women and 9.2% in men over 7 years. The likelihood of developing diabetes increased per SD decrease (19%) from the 7-year population mean change (−8.3%) in women (HR 1.22 [95% CI 1.09–1.39]) and men (1.45 [1.20–1.75]) after adjustment for age, race, smoking, family history of diabetes, baseline fitness, BMI, and fasting glucose. Participants who developed diabetes over 20 years experienced significantly larger declines in relative fitness over 20 years versus those who did not.
Low fitness is significantly associated with diabetes incidence and explained in large part by the relationship between fitness and BMI.
PMCID: PMC2699748  PMID: 19324945
19.  An Association between Clotting Factor VII and Carotid Intima-Media Thickness: The CARDIA Study 
To investigate associations of procoagulants (FVII, FVIII, von Willebrand factor [vWF]) with subclinical atherosclerosis, we examined participants in The Coronary Artery Risk Development in Young Adults (CARDIA) Study.
Clotting factor assays were performed in 1254 participants ages 23–37 (baseline) and repeated at ages 38–50 (follow-up). Carotid intima-media thickness (IMT) was measured at follow-up.
Baseline levels of procoagulants (%): mean (SD) were: FVII: 76(18), FVIII: 102(38), and vWF: 108(47). At follow-up, all had increased by 40%–55%. After age adjustment, mean common carotid (CC) IMT increased from the lowest to the highest tertile of FVII in the total group (0.787 to 0.801, P=0.007), in whites (0.772 to 0.790, P=0.002), and in men (0.807 to 0.827, P=0.015). All associations were attenuated by multivariable adjustment. However, participants with FVII values in the highest tertile at one or both examinations, as compared with those in the lowest tertile, had greater CC-IMT after age and multivariable adjustment (0.806 versus 0.778, P<0.05). Baseline FVIII was associated with greater internal carotid (IC) IMT in the total group, in whites, and in women after age but not multivariable adjustment. No associations were seen for vWF.
FVII is associated with CC-IMT in young adults, but the strength of the association is modified by other cardiovascular disease risk factors, such as body mass index. FVIII is associated with IC IMT only in age-adjusted analyses, and no associations were observed for vWF.
PMCID: PMC2894290  PMID: 20466994
Factor VII; Carotid Thickening; Atherosclerosis; Factor VIII
20.  Elevated Fibrinogen Levels and Subsequent Subclinical Atherosclerosis: The CARDIA Study 
Atherosclerosis  2008;202(2):623-631.
To determine whether elevated levels of hemostatic factors are associated with the subsequent development of subclinical cardiovascular disease.
Fibrinogen, factors VII (FVII) and VIII (FVIII), and von Willebrand factor (vWF) were measured in 1396 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Coronary artery calcification (CAC) and carotid intimal/medial thickness (CIMT) were determined 13 years later. The adjusted prevalence of CAC and mean CIMT across the quartiles of each hemostatic factor was computed for the total sample and for each race and gender group.
The age, race, and gender-adjusted prevalences of CAC with increasing quartiles of fibrinogen were 14.4%, 15.2%, 20.0%, and 29.1% (p<0.001 for trend). This trend persisted after further adjustment for body mass index (BMI), smoking, educational level, center, systolic blood pressure (BP), diabetes, antihypertensive medication use, total and high density lipoprotein (HDL) cholesterol, and CRP. A similar trend was observed for CIMT (age, race and gender-adjusted, p<0.001; multivariable-adjusted, p=0.014). Further analyses of race and gender subgroups showed that increasing quartiles of fibrinogen were associated with CAC and CIMT in all subgroups except black men. The prevalence of CAC was not associated with increasing quartiles of FVII, FVIII or vWF, suggesting they may be less involved in plaque progression.
An elevated fibrinogen concentration in persons aged 25 to 37 is independently associated with subclinical cardiovascular disease in the subsequent decade.
PMCID: PMC2662501  PMID: 18602107
hemostatic factors; coronary calcium; carotid thickness; fibrinogen; atherosclerosis
21.  Racial Differences in Self-Reported Infertility and Risk Factors for Infertility in a Cohort of Black and White Women: The CARDIA Women’s Study 
Fertility and sterility  2008;90(5):1640-1648.
To determine racial differences in self-reported infertility and in risk factors for infertility in a cohort of black and white women.
A cross-sectional analyses of data from the longitudinal Coronary Artery Risk Development in Young Adults (CARDIA) Study, a prospective, epidemiologic investigation of the determinants and evolution of cardiovascular risk factors among black and white young adults and from the ancillary CARDIA Women’s Study (CWS).
Population-based sample from 4 US communities (Birmingham, AL; Chicago, IL, Minneapolis, MN; and Oakland, CA).
Women ages 33–44 who had complete data (n=764).
Main Outcome Measure
Self-report of ever having unprotected sexual intercourse for at least 12 months without becoming pregnant.
Among non-surgically sterile women, blacks had a two-fold increased odds (95% CI = 1.3–3.1) of infertility as compared with whites after adjustment for socioeconomic position (education and ability to pay for basics), correlates of pregnancy intent (marital status and hormonal contraceptive use), and risk factors for infertility (age, smoking, testosterone, fibroid presence, and ovarian volume). The corresponding OR among all women was 1.5 (95% CI 1.0–2.2). Difficulty paying for basics and ovarian volume were associated with infertility among black but not white women.
In this population-based sample, black women were more likely to have experienced infertility. This disparity is not explained by common risk factors for infertility such as smoking and obesity, and among non-surgically sterile women, it is not explained by gynecologic risk factors such as fibroids and ovarian volume.
PMCID: PMC2592196  PMID: 18321499
Infertility; race; ethnicity; disparity; fibroids; ovarian volume
22.  Sex Hormones, Sex Hormone Binding Globulin, and Abdominal Aortic Calcification in Women and Men in the Multi-Ethnic Study of Atherosclerosis (MESA) 
Atherosclerosis  2008;200(2):432-438.
Conflicting findings exist regarding the associations of sex hormones with subclinical atherosclerosis.
This is a substudy from MESA of 881 postmenopausal women and 978 men who had both abdominal aortic calcification (AAC) quantified by computed tomography and sex hormone levels assessed [Testosterone (T), estradiol (E2), dehydroepiandrosterone (DHEA), and sex hormone binding globulin (SHBG)]. We examined the association of sex hormones with presence and extent of AAC.
For women, SHBG was inversely associated with both AAC presence [OR=0.62, 95% CI 0.42 to 0.91 for 1 unit greater log(SHBG) level] and extent [0.29 lower log(AAC) for 1 unit greater log(SHBG) level, β= −0.29 (95% CI −0.57 to −0.006)] adjusting for age, race, hypertension, smoking, diabetes, BMI, physical activity, and other sex hormones. After further adjustment for total and HDL-cholesterol, SHBG was not associated with ACC presence or extent. In men, there was no association between SHBG and AAC. In both men and women, neither T, E2, nor DHEA was associated with AAC presence or extent.
After adjustment for non-lipid cardiovascular risk factors, SHBG levels are inversely associated with both the presence and severity of AAC in women but not in men, which may be accounted for by HDL.
PMCID: PMC2607033  PMID: 18262187
sex hormone binding globulin; abdominal aortic calcification; sex hormones; subclinical atherosclerosis
23.  Low-Density Lipoprotein and High-Density Lipoprotein Cholesterol Levels in Relation to Genetic Polymorphisms and Menopausal Status: The Atherosclerosis Risk In Communities (ARIC) Study 
Atherosclerosis  2008;200(2):322-328.
Genes coding for proteins involved in lipid metabolism and, in women, menopausal status are independently associated with high-density lipoprotein cholesterol (HDL-c) and low-density lipoprotein cholesterol (LDL-c) levels. We examined whether the association between common functional genetic polymorphisms of apolipoprotein E (apoE Cys112Arg and Arg158Cys) gene and LDL-c levels, as well as the associations between the cholesteryl ester transfer protein (CETP TaqIB), hepatic lipase (LIPC C-514T), and lipoprotein lipase (LPL Ser447Stop) genes and HDL-c levels are significantly modified by menopausal status. Plasma lipid concentrations, genotype, and menopausal status were assessed across four examinations in a sample of Caucasian and African-American women (n=4652 to 4876) who were aged 45-64 years at baseline from the Atherosclerosis Risk in Communities Study. The association between LDL-c levels and the apoE gene, and HDL-c levels and the LIPC and LPL genes were not modified by menopausal status. The only statistically significant gene by menopause interaction was with the CETP gene on HDL-c concentrations (p=0.04). However, the significant CETP gene by menopause interaction was possibly due to chance because of multiple testing. Postmenopausal women who were carriers of the A allele of the CETP gene had approximately 0.7 mg/dL lower HDL-c levels than pre-/perimenopausal counterparts, whereas the opposite pattern of HDL-c (0.4 mg/dL higher HDL-c postmenopausally) was observed for the GG genotype. Overall, our data suggest that the decrease in endogenous estrogen as a result of menopause may independently affect lipoprotein concentration, but does not alter the effect on plasma lipids of some common genetic polymorphisms that regulate lipoprotein metabolism.
PMCID: PMC2583258  PMID: 18275964
LDL; HDL; apolipoprotein E; cholesteryl ester transfer protein; hepatic lipase; lipoprotein lipase; menopause
24.  Association of Acculturation Levels and Prevalence of Diabetes in the Multi-Ethnic Study of Atherosclerosis (MESA)  
Diabetes Care  2008;31(8):1621-1628.
OBJECTIVE—The prevalence of type 2 diabetes among Hispanic and Asian Americans is increasing. These groups are largely comprised of immigrants who may be undergoing behavioral and lifestyle changes associated with development of diabetes. We studied the association between acculturation and diabetes in a population sample of 708 Mexican-origin Hispanics, 547 non–Mexican-origin Hispanics, and 737 Chinese participants in the Multi-Ethnic Study of Atherosclerosis (MESA).
RESEARCH DESIGN AND METHODS—Diabetes was defined as fasting glucose ≥126 mg/dl and/or use of antidiabetic medications. An acculturation score was calculated for all participants using nativity, years living in the U.S., and language spoken at home. The score ranged from 0 to 5 (0 = least acculturated and 5 = most acculturated). Relative risk regression was used to estimate the association between acculturation and diabetes.
RESULTS—For non–Mexican-origin Hispanics, the prevalence of diabetes was positively associated with acculturation score, after adjustment for sociodemographics. The prevalence of diabetes was significantly higher among the most acculturated versus the least acculturated non–Mexican-origin Hispanics (prevalence ratio 2.49 [95% CI 1.14−5.44]); the higher the acculturation score is, the higher the prevalence of diabetes (P for trend 0.059). This relationship between acculturation and diabetes was partly attenuated after adjustment for BMI or diet. Diabetes prevalence was not related to acculturation among Chinese or Mexican-origin Hispanics.
CONCLUSIONS—Among non–Mexican-origin Hispanics in MESA, greater acculturation is associated with higher diabetes prevalence. The relation is at least partly mediated by BMI and diet. Acculturation is a factor that should be considered when predictors of diabetes in racial/ethnic groups are examined.
PMCID: PMC2494621  PMID: 18458142
25.  Ethnic Differences in the Relationship of Carotid Atherosclerosis to Coronary Calcification: The Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2007;197(1):132-138.
Ethnic differences in non-invasive measures of atherosclerosis are increasingly being reported, but the relationship of these measures to each other has not been widely explored. Carotid ultrasonographic and computed cardiac tomographic findings were compared in 6,814 participants of White, Black, Hispanic, and Chinese ethnicities free of overt cardiovascular disease. Coronary calcium and carotid atherosclerosis were strongly related to each other in all ethnic groups. Associations of coronary calcium prevalence and common carotid intimal-medial thickness (IMT) differed by ethnicity in women, being weakest among Black women (0.07 mm IMT difference between those with and without coronary calcium) compared to the other three groups (0.10–0.12 mm difference, p = 0.007). Estimated percent increments in internal carotid IMT per 10% increment in coronary calcium score were highest in Hispanics (18.5%) and lowest in Blacks (6.1%, p < 0.01).
Coronary calcium may be less strongly associated with carotid atherosclerosis in Blacks, particularly Black women, than in other ethnic groups. These differences should be pursued for relationships to coronary events to determine whether coronary calcium carries the same risk information in other ethnic groups as it does in Whites.
PMCID: PMC2314669  PMID: 17412347
atherosclerosis; calcium; carotid arteries; epidemiology

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