Methods

The Johns Hopkins Medicine institutional review board approved the GeneSTAR study, which has been previously described. In brief, given that siblings of those with premature CAD have a more than twofold excess risk of CAD, GeneSTAR was designed to explore CAD risk factors in a cohort of high-risk families (available at: www.genestarstudy.com ). Probands with documented early-onset (age <60 years) CAD events, including myocardial infarction (42.9%), coronary artery bypass surgery (21.2%), percutaneous coronary intervention (22.6%), or ≥50% stenosis in ≥1 vessels confirmed on a coronary angiogram with or without angina symptoms (13.1%), were identified at hospitalization for the sentinel CAD event. Their apparently healthy siblings aged <60 years and free of known CAD were recruited and screened from 1985 to 2007. Siblings were excluded from the study for systemic autoimmune disease, chest radiation exposure, any life-threatening disease (acquired immunodeficiency syndrome or advanced cancer), or long-term glucocorticosteroid therapy.

All participants gave written informed consent before screening. Demographic information (age, gender, race, education, marital status) was obtained from standardized self-administered questionnaires. Siblings who self-reported smoking any cigarettes within the previous month or who had an expired carbon monoxide ≥8 ppm on 2 successive measurements were considered to be current smokers.

Medical history, including current prescription and over-the-counter medication use, was obtained by a physician and a nurse, and a physical examination was performed by a cardiologist. A history of any psychiatric disorder was considered present if any report was present of a current or previous psychiatric diagnosis by a physician, licensed counselor, or psychologist according to the “Diagnostic and Statistical Manual of Mental Disorders, 4th edition.” Psychiatric medication use was considered present if the current use of any medications used explicitly for psychiatric or mental problems was recorded.

Blood was obtained after the participants had fasted for ≥8 hours overnight. The total and high-density lipoprotein (HDL) cholesterol, triglycerides, and glucose levels were measured directly using Clinical Laboratory Improvements Amendments-approved standardized methods in the Johns Hopkins Analytical Chemistry Laboratory. Low-density lipoprotein (LDL) cholesterol was calculated using the Chen formula. Diabetes was defined as a self-reported physician’s diagnosis of current diabetes, current use of insulin or hypoglycemic medication, and/or fasting glucose level >125 mg/dl (6.9 mmol/L).

Blood pressure was measured 3 times during the course of the 8-hour screening day using standard guidelines and averaged to represent the blood pressure at rest. Hypertension was defined as a blood pressure at rest of ≥140/90 mm Hg and/or current antihypertensive medication use. The weight and height were measured, and the body mass index was calculated as the weight (kg) divided by the height (m ² ). Maximal graded treadmill tests were performed using a standardized modified Bruce protocol; the total metabolic equivalent task levels were calculated as the minutes on the treadmill multiplied by the metabolic equivalent task level associated with the achieved stage of the protocol, expressed as MET-minutes and used to characterize cardiorespiratory fitness. The 10-year FRSs were calculated according to established criteria inclusive of gender, age, total and HDL cholesterol, systolic and diastolic blood pressure, diabetes, and smoking. The siblings were placed into low-risk (<10%), intermediate-risk (10% to 20%), and high-risk (>20%) groups.

The GWBS was self-administered and reviewed for completion. The GWBS questionnaire was originally designed to measure self-report of subjective well-being in normal populations. The instrument consists of 18 items, representing 6 psychological domains: relaxed versus tense (anxiety), cheerful versus depressed mood (depression), freedom from health concern (somaticism), energy level (vitality), life satisfaction, and emotional-behavioral control. The domain scores sum to a total score with a maximum of 110 points, with greater scores representing greater “positive well-being.” The GWBS total score has good internal consistency (Cronbach’s alpha 0.90 to 0.94) and test–retest reliability. It has been used to characterize healthy populations in several large clinical and epidemiologic studies, including NHANES I, and has been validated in European- and African-American populations. The instrument and scoring system are available online.

The siblings completed a standardized health status and cardiovascular disease event questionnaire at approximately 5-year intervals after their baseline visit with trained telephone interviewers from 1992 to 2012. For deceased siblings, proxy interviews were completed with the next of kin. The medical records were then obtained for all reports of a CAD event, any possibly related diagnosis, diagnostic procedure (including exercise tests, thallium imaging, or coronary angiography), and therapeutic procedure. Medical record documentation was reviewed, and CAD events were classified independently by 2 cardiologists and 1 epidemiologist, each unaware of the review of the others, according to a standardized Framingham Heart Study schema. Whenever discordance was present among the team, an external adjudication committee consisting of ≥1 nonstudy cardiologist from Johns Hopkins and 1 from another institution reviewed and adjudicated the final event classification. For participants with >1 documented event, only the first event was used in the present analysis.

Detailed descriptions of NHANES I and the NHEFS have been previously published. In brief, NHANES I was conducted from 1971 to 1975 in the United States by the National Center for Health Statistics, Centers for Disease Control and Prevention (Bethesda, Maryland), to obtain the national estimates on the health and nutritional status of the United States population. NHANES I was based on a complex, multistage, stratified, clustered, probability-sample design and included a representative sample of the noninstitutionalized civilian United States population living in households. The NHEFS was a national longitudinal study that included studies from 1982, 1987, and 1992 designed to investigate the relations among the factors assessed in NHANES I and subsequent morbidity, mortality, and hospital usage.

The present study used data from the NHANES I examination sample of adults aged 25 to 74 years. In brief, the participants received standardized interview questionnaires to obtain the sociodemographic data. Additional information included smoking, medical history (medication use, diagnosis of diabetes or hypertension, history of psychiatric condition), and physical activity questions. Current smokers were defined as those who self-reported that they currently smoked cigarettes. Diabetes, hypertension, and psychiatric diseases were defined as a self-reported physician diagnosis and/or medication use. A question asking the level and intensity of recreational physical activity was used to categorize fitness as none to little, moderate, or high physical activity. NHANES I also obtained standardized measurements of height and weight; the body mass index was calculated by dividing weight (kg) by height (m ² ). Blood was drawn in mobile examination centers, and the total serum cholesterol was measured by the Centers for Disease Control and Prevention laboratory (Bethesda, Maryland) using standardized methods; the HDL and LDL cholesterol levels were unavailable. The GWBS was administered in the mobile examination centers by trained interviewers.

CAD events were identified from the hospital and/or nursing home discharge reports and death certificates. CAD was recorded if the “International Classification of Diseases, 9th revision” codes 410 to 414 were listed. For nonfatal events, the date of the CAD event was the date of admission obtained in the discharge report or self-reported, if not available on the record. The date of a fatal CAD event was the date of death recorded from the death certificate. For participants with >1 event, only the earliest event was included.

A total of 6,913 adults, aged 25 to 74 years, were interviewed, received a detailed physical and medical examination, and were eligible for the present analyses. After excluding 921 subjects with missing covariates and missing outcome information, 5,992 (86.7% of those eligible) were included in the present analyses.

The data were analyzed using Statistical Analysis Systems, version 9.2 (SAS Institute, Cary, North Carolina), STATA, version 11 (StataCorp, College Station, Texas), and R, version 2.12.1 (R Foundation for Statistical Computing, Vienna, Austria, 2012). For the bivariate analyses, frequencies and contingency table arrays and the chi-square statistic were used; for continuous and ordinal variables, Student’s t tests and the Wilcoxon rank-sum test were used. Psychometric properties of the GWBS were assessed using measures of internal consistency, Cronbach’s alpha and item-to-total correlations. Continuous variables were standardized by dividing by their standard deviations before entry in the regression models. Hazard ratios (HRs) and 95% confidence intervals (CIs) of CAD events were estimated using Cox proportional hazards regression modeling for incident CAD, adjusting for age, gender, race, education, marital status, current smoking, diabetes, hypertension, LDL and HDL cholesterol, body mass index, physical fitness, having a psychiatric diagnosis and/or medication use, and GWBS. For GeneSTAR, we implemented a grouped jackknife estimation, in which the variance of HRs is empirically estimated by a set of regressions, leaving 1 family cluster out at a time, implicitly accounting for the nonindependence of the time to event within families. This method is appropriate for censored time-to-event analyses, because explicit modeling of within-cluster correlation of censored variables, which is required for generalized estimating equation methods, is not possible. Sensitivity analyses examined the same regression analyses with the exclusion of participants with psychological diagnoses and/or medication use. Separate regression analyses for each dichotomous group (men and women; European- and African-Americans; hypertensives and nonhypertensives; diabetics and nondiabetics; smokers and nonsmokers; married and nonmarried; obese and nonobese; high school and less than high school education; psychiatric diagnosis and/or medication use and no diagnosis or medication use; age <46 and ≥46 years; HDL <40 and ≥40 mg/dl; LDL <160 and ≥160 mg/dl; MET-minutes less than the median [83] and the median or greater) and separate regression analyses with each potentially influential variable expressed as present or absent were included with an interaction term with the GWBS total score. FRS analyses were performed separately within each FRS strata with the same adjustments as for the primary model.

Results

We screened 1,504 siblings at baseline and obtained outcomes data for 98.6% or 1,483 siblings, who were included in the present study sample. The siblings came from 778 families, with a mean of 1.9 ± 1.2 siblings per family (range 1 to 9) and a mean of 12.1 ± 6 years of follow-up (range 5 to 25). The GWBS was highly internally consistent, with a Cronbach alpha of 0.91 for the GWBS total score and ranging from 0.61 to 0.83 for the domain scores.

During follow-up, we documented 208 incident CAD events (overall rate 14%), with 71 of 208 (34.1%) classified as “hard” events (myocardial infarction or sudden death). Unstable angina with >50% coronary luminal stenoses occurred in 38.5% of the subjects, 77.5% of whom underwent revascularization. Chronic stable angina with >50% stenosis in ≥1 coronary vessel occurred in 27.4%, 68% of whom underwent revascularization. The mean interval from baseline to an incident CAD event was 8.2 ± 5.4 years (median 7.1). The mean age at the event was 56.2 ± 7.6 years (range 34 to 74). Incident events occurred in 68 of 834 women (8.2%) and 140 of 649 men (21.6%).

The baseline demographic and risk characteristics for those with and without an incident CAD event are listed in Table 1 . The presence of a psychiatric diagnosis (4.3% depression; 0.68% anxiety) or prescribed psychiatric medications was relatively low. Psychiatric pharmacotherapy included 3.8% taking benzodiazepines, 4.5% taking selective serotonin reuptake inhibitors, and 0.9% taking both agents.

The GWBS total and domain scores by CAD event status are listed in Table 2 . The unadjusted HR for incident CAD related to greater GWBS total scores was 0.77 (95% CI 0.68 to 0.87). Multivariate survival analysis showed that greater GWBS total scores were associated with a significantly lower risk of incident CAD, independent of all risk factors and salient variables ( Table 3 ). Every 16-point increase in the baseline GWBS total score was associated with a 33% reduction in incident CAD risk, even after accounting for important risk factors and covariates.

Table 3

Multivariate Cox proportional hazards model predicting incident coronary artery disease (CAD) in GeneSTAR (n = 1,483) ^∗

Characteristic	HR (95% CI)	p Value
Baseline age (yrs) †	1.38 (1.18–1.61)	<0.0001
Male gender	2.87 (2.03–4.06)	<0.0001
African-American race	0.51 (0.35–0.74)	0.0004
Hypertension	1.65 (1.19–2.30)	0.003
LDL cholesterol (mg/dl) †	1.31 (1.15–1.49)	<0.0001
HDL cholesterol (mg/dl) †	0.85 (0.70–1.04)	0.11
Diabetes mellitus	1.99 (1.25–3.16)	0.0036
Current smoker	1.36 (0.99–1.87)	0.06
General well-being (total score) †	0.67 (0.58–0.79)	<0.0001

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