Table 1. Demographics and Clinical Data by Age Group (HHP Exam: 1991–1994)

Age Group 71–74 75–79 80–84 85þ p Value Risk Factors (N ¼ 1063) (N ¼ 1453) (N ¼ 668) (N ¼ 378) for Trend Age 73.07 6 0.88 76.78 6 1.4 81.65 61.4 87.3 6 2.0 NA BMI (kg/m2) 24.22 6 2.97 23.59 6 3.13 22.73 6 3.01 22.03 6 3.23 ,.0001 Alcohol (oz/mo) 20.76 6 44.74 19.41 6 39.47 15.78 6 33.46 15.32 6 39.36 .0152 Smoking (pack-years) 28.43 6 34.93 28.03 6 34.86 21.83 6 33.51 18.36 6 30.08 ,.0001 Physical activity index 31.62 6 4.81 30.94 6 4.62 30.36 6 4.34 29.43 6 4.17 ,.0001 Hypertension, % 73 74 74 72 .8602 Systolic BP (mmHg) 146.01 6 20.87 149.39 6 23.22 152 6 24.39 154.34 6 28.97 ,.0001 Diabetes, % 28 30 29 26 .4066 Glucose (mg/dL) 113.27 6 28.18 114.07 6 30.3 112.65 6 29.36 109.33 6 29.3 .0155 Total cholesterol (mg/dL) 193.55 6 32 190.62 6 32.4 188.08 6 35.13 178.24 6 31.54 ,.0001 TG (mg/dL) 153.46 6 87.96 151.35 6 92.43 140.42 6 79.99 130.59 6 79.08 ,.0001 LDL-C (mg/dL) (computed) 114.11 6 30.61 110.44 6 30.27 108.42 6 32.29 101.24 6 29.22 ,.0001 HDL-C (mg/dL) 49.68 6 12.36 51.08 6 13.6 52.18 6 14.11 51.73 6 13.49 .0034 HDL-C . 60 mg/dL, % 20 23 26 23 .1226

from http://biomedgerontology.oxfordjournals.org/ by guest on March 20, 2016

NA ¼ not applicable; HHP ¼ Honolulu Heart Program; BMI ¼ body mass index; BP ¼ blood pressure; TG ¼ triglycerides; LDL-C ¼ low-density lipoprotein cholesterol; HDL-C ¼ high-density lipoprotein cholesterol.

was separated by precipitation with dextran sulfate and magnesium chloride (18). Lipids were measured using an Olympus Demand System (Olympus Corp., Lake Success, NY). DNA was obtained from white blood cells separated from plasma samples. The Int 14A and D442G variants (rs5742907 and rs2303790, respectively) in the CETP gene were identified by polymerase chain reaction amplification and primer-specific restriction map modification, as pre- viously described (19).

was found between age and the percentage of participants with HDL-C .60 mg/dL.

During the 8-year follow-up, there were 1080 deaths from all causes, including 349 CVD deaths. Higher (.60 mg/dL) HDL-C levels were significantly (p ¼ .0016) associated with a lower rate of CVD mortality after adjustment for age (Table 2). Non-CVD deaths were positively associated with higher HDL-C levels after age adjustment (p ¼ .0228). However, with adjustments for additional common risk factors (age, smoking, hypertension, alcohol intake, BMI, total cholesterol, diabetes, and physical activity index), the relative risk of non-CVD deaths was no longer associated with HDL-C levels (Table 3). The relative risk of CVD deaths remained strongly associated (p ¼ .002) with HDL-C level after the same adjustments. Higher HDL-C level was associated with healthy aging in participants older than 90 years (p ¼ .047; Table 4).

Statistical Methods

age group and the test of trends for age were calculated using the General Linear Model. The age-specific and age- adjusted rates of total mortality, CVD deaths, and other deaths for HDL-C levels and CETP variants were calculated in person-years. The differences between rates were tested using Cox’s proportional hazard model, which was also used to estimate the relative risk for the linear effects of the HDL-C on total and cause-specific mortalities, adjust- ing for age, smoking, hypertension, alcohol intake, BMI, cholesterol level, diabetes, and physical activity index. Age-adjusted mean levels of HDL and frequencies of the Int 14A variant by healthy aging status were estimated using analysis of covariance. Fisher’s exact test was used to compare proportions of healthy survivors across Int 14A genotypes. The statistical software SAS (version 9; SAS Institute Inc, Cary, NC) was used in the statistical analysis.

Of the 3448 men genotyped for CETP, 17 had the Int 14A mutation. Although a trend suggested decreased all-cause mortality for men with the Int 14A variant compared to those without the variant, the association failed to reach statistical significance (p ¼ .20; Figure 1), possibly due to the small number of participants, which provided 13.9% power to detect a difference of this magnitude at the 5% level. However, of men who were considered healthy at

Table 2. Age-Adjusted Total and Cause-Specific Mortalities by HDL-C Level

HDL-C Level Age-Adjusted Rates p Value for Deaths (mg/dL) (Deaths/1000 PY) Adjusted Rates Total ,60 51.26 .946 .60 50.91 CVD ,60 17.94 .0016 .60 11.45 Non-CVD ,60 33.32 .0228 .60 39.46

R ESULTS

BMI, alcohol consumption, smoking, physical activity index, fasting serum glucose, total cholesterol, and TG levels had significant negative associations with age (Table 1). Systolic BP levels increased significantly (p , .0001) with increasing age, but no trend was found relating age to hypertension. HDL-C levels increased significantly (p ¼ .0034) with age. Of the 3562 participants analyzed for HDL-C, 22.7% had levels .60 mg/dL. No association

Note: HDL-C ¼ high-density lipoprotein cholesterol; PY ¼ person-years; CVD ¼ cardiovascular disease.

Table 4. Evaluation of Healthy Aging in Participants Surviving to .90 Years

Table 3. Relative Risk of Mortality for Men by HDL-C Level

Cause of Death Relative Risk* 95% CI p Value Total 0.998 0.99–1.004 .547 CVD 0.984 0.974–0.994 .002 Non-CVD 1.005 0.998–1.011 .147

Unhealthy or Deceased Variable Healthy Before Age 90 p Value No. of participants 123 1520 NA Average age* 83.3 (63.5) 76.1 (63.5) NA HDL-C level (mg/dL)* 54.0 (614.2) 51.2 (612.6) .047 Int 14A mutation, %y 2.7 0.4 .005

Notes: *Adjusted for age and risk factors (smoking, hypertension, alcohol intake, body mass index, total cholesterol, diabetes, and physical activity index). HDL-C ¼ high-density lipoprotein cholesterol; CI ¼ confidence interval; CVD ¼ cardiovascular disease.