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A Prospective Study of High-Density Lipoprotein Cholesterol, Cholesteryl Ester Transfer Protein Gene Variants, and Healthy Aging in Very Old Japanese-American Men

¹ Pacific Health Research Institute, Honolulu, Hawaii.
² John A. Burns School of Medicine, University of Hawaii at Manoa.
³ Kuakini Medical Center, Honolulu, Hawaii.

Address correspondence to J. David Curb, MD, Pacific Health Research Institute, 846 South Hotel St., Suite 301, Honolulu, Hawaii, 96813. E-mail: jdcurb{at}phrihawaii.org

	Abstract

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Background. High-density lipoprotein cholesterol (HDL-C) and cholesteryl ester transfer protein (CETP) gene deficiency mutations that increase HDL-C levels have been associated with exceptional longevity. However, a recent clinical trial of a promising CETP inhibitor that markedly increases HDL-C was terminated due to increased mortality. In light of this controversy, we examined the relationship among HDL-C, CETP mutations, and longevity phenotypes in the long-lived Japanese-American men of the Honolulu Heart Program (HHP).

Methods. Japanese-American men (n = 3562) were followed for up to 8 years, from average age 78 to average age 84 (maximum age 99), or until death. Total mortality, cause-specific mortality, and healthy survival were evaluated for associations with HDL-C level and CETP genetic variants common in the Japanese population (CD442G and Int 14A).

Results. HDL-C was negatively associated with cardiovascular disease (CVD) mortality (p =.002) but not related to non-CVD (p =.147) or total (p =.547) mortality after adjustment for common risk factors. There was a trend for lower mortality for the men with the Int 14A variant. These men also had higher HDL-C levels (p =.047) and were significantly more likely to be healthy survivors (absence of six major age-related diseases and high physical/cognitive function) beyond the age of 90 years (p =.005).

Conclusions. Low HDL-C level is a risk factor for CVD mortality in elderly Japanese-American men. High HDL-C and the Int 14A variant of the CETP gene may increase odds for healthy aging.

Key Words: High-density lipoprotein cholesterol (HDL-C) • Cholesteryl ester transfer protein (CETP) • Japanese Americans • Cardiovascular disease • Longevity • Healthy aging

Recent findings suggest that a favorable lipoprotein profile, including high levels of high-density lipoprotein (HDL) and low levels of low-density lipoprotein (LDL), is predictive of exceptional longevity, likely due in part to reduction in CVD risk (4). Certain variants in genes involved in lipoprotein metabolism have also been linked to exceptional longevity (4–6). One of these is the cholesteryl ester transfer protein (CETP) gene, which codes for a carrier in reverse cholesterol transport that mediates the transfer of cholesteryl esters from HDL to LDLs and triglyceride (TG)-rich lipoproteins (7). Several naturally occurring mutations in the CETP gene lead to dramatic reductions in plasma CETP levels and a significant increase in HDL-cholesterol (HDL-C) levels. The most common missense variation (I405V) is known to be over-represented in Ashkenazi Jewish centenarians and their offspring (4). Centenarians and their offspring had an approximate 2- to 3-fold increased frequency of homozygosity for the codon 405 isoleucine to valine (I405V) gene variant of CETP (VV genotype).

Given that a reduction in CETP level leads to dramatic increases in HDL-C, a new class of CETP inhibitor drugs was developed for use in combination with LDL-C-lowering statins to improve lipoprotein profiles and decrease CVD risk in patients with dyslipidemia (8). However, in late 2006, a clinical trial of the CETP inhibitor torcetrapib was halted due to increased mortality in persons taking the drug (9). This development underscores the need for further investigation into the relationship among CETP, HDL-C levels, and health outcomes.

Previously we reported that 5.6% of the Japanese-American men of the Honolulu Heart Program (HHP) have either the D442G (5.1%) or the Int 14A (0.51%) mutation in the CETP gene (10). These variants are common in the general Japanese population and appear to explain a significant portion of the variation in HDL-C levels (11). In our prior work these mutations were associated with a 35% decrease in plasma CETP levels and a significant (p <.001) increase in HDL-C levels. More recently, a 7-year follow-up study of the now elderly HHP participants (71–93 years) revealed that the relative risk of CHD incidence is significantly (p <.05) lower for men with high (>60 mg/dL) HDL-C levels (12). A trend also suggested that men with either the D442G or Int 14A CETP mutations have a lower incidence of CHD.

Interestingly, many risk factors can be linked to a single disease, but fewer protect against multiple age-related diseases and disability. HDL has been proposed as a protector against both CVD and dementia, two phenotypes important for healthy aging. However, little is known about how HDL and gene variants that affect HDL might affect other phenotypes that represent healthy aging and longevity. Therefore, the current study investigates the relationship of HDL-C level and CETP mutations to several aging- and longevity-related phenotypes including total mortality, CVD mortality, non-CVD mortality, and a novel phenotype of healthy aging that incorporates multiple diseases, physical function, and cognitive function. This novel phenotype is defined by exceptional survival to age 90 years or more while remaining free of six major chronic diseases and maintaining high physical and cognitive function.

	METHODS

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Participants and General Procedures
The HHP, initiated in 1965, is an ongoing prospective study of heart disease, stroke, and other diseases in a sample of 8006 men of Japanese ancestry in Hawaii. These men were recruited from 9877 men (all ethnic Japanese men with valid contact information), who were born between 1900 and 1999, and lived on the island of Oahu (13). Participants received comprehensive examinations at the time of enrollment, when they were 45–68 years old (mean age 54 years). Since that time, participants have undergone nine repeat examinations during which phenotypic information has been obtained by physical and cognitive examinations and cross-checked with medical records and self report. Follow-up of all hospital discharges, death certificates, and autopsy records for morbidity and mortality due to CHD, cancer, and stroke has been performed for all participants. A follow-up survey for HHP Exam 4 (1991–1993) found that only five men could not be traced for mortality information (14). Written informed consent has been obtained from all study participants. Procedures used in the HHP are performed in accordance with institutional guidelines, are approved by an institutional review board, and are described in detail elsewhere (15).

The baseline examination for this study was HHP Exam 4, which was carried out between 1991 and 1994 on the surviving HHP participants as part of the Honolulu Asia Aging Study (HAAS), a study of cognitive aging (mean baseline age 78 years, range 71–93 years). The measurements taken at this examination provide the baseline clinical data for this study. There are two follow-up periods: total mortality data are available until 2005, which provide 11–14 years of follow-up. For cause-specific mortality, which is updated less frequently due to its adjudication by a morbidity and mortality committee, the follow-up is 5–8 years. Risk factors measured at baseline included body mass index (BMI), alcohol consumption, smoking habits (pack years), physical activity [as measured by the physical activity index (16)], hypertension, systolic blood pressure (BP), diabetes, and fasting levels of serum glucose, total serum cholesterol, TG, and HDL-C. A diagnosis of hypertension was made when either systolic BP was 140 mmHg or diastolic BP was 90 mmHg or when the participant was taking medication for high BP. Diabetes was defined on the basis of medical history or the use of insulin or oral hypoglycemic agents. Diabetes was also considered present when fasting glucose concentrations were >125 mg/dL or when glucose levels were 200 mg/dL 2 hours after ingestion of 75-g glucose.

Healthy aging was defined as survival beyond the age of 90 years with the absence of six major age-related diseases (CHD, stroke, cancer, chronic obstructive pulmonary disease, Parkinson's disease, and type 2 diabetes mellitus), ability to walk half a mile, and absence of cognitive disability as determined by a Cognitive Abilities Screening Instrument (CASI) score > 74 (17).

Participants were excluded from analyses if serum cholesterol levels or CETP genotyping data were not available, resulting in a total study population of 3562 participants for HDL-C level comparisons, and 3448 participants for the CETP association analysis. For the healthy aging analysis, to achieve a true incidence study, all participants who were determined to be unhealthy at baseline (prevalence of any one of six major diseases, could not walk a half mile, or had CASI score 74) were excluded from the sample, and the remaining 1643 healthy participants were followed until they reached age 90 years or more or died.

Laboratory Analyses
Methods for preparing blood samples for analysis followed the guidelines of the Lipid Standardization Laboratory of the Centers for Disease Control and Prevention. Blood samples were collected after an overnight fast of at least 12 hours. Blood was centrifuged within 30 minutes of collection at 3000 x g for 10 minutes at 4°C, and the plasma was frozen at –70°C for up to 2 months. Samples were shipped to the University of Vermont, where HDL-C 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 previously described (19).

Statistical Methods
The characteristics of the study participants at baseline by 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, adjusting 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.

	RESULTS

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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 =.0034) with age. Of the 3562 participants analyzed for HDL-C, 22.7% had levels >60 mg/dL. No association was found between age and the percentage of participants with HDL-C >60 mg/dL.

View larger version (15K): [in this window] [in a new window]   Figure 1. Age-adjusted all-cause mortality for men with (+) and without (–) the Int 14A variant of the cholesteryl ester transfer protein (CETP) gene. PY = person years. p =.20

	DISCUSSION

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The present study reports that age and CVD risk factor-adjusted HDL-C levels are negatively associated with CVD-related mortality, but not total mortality, in this elderly population. Age-adjusted HDL-C levels were also positively associated with non-CVD mortality; however, this trend was lost with further adjustments for selected CVD risk factors. A healthy aging advantage was found for individuals with higher levels of HDL-C and for individuals with the Int 14A variant in the CETP gene. Furthermore, a nonsignificant trend indicated that men with the Int 14A variant may also have an overall survival advantage. Taken together, these data support prior findings that gene variants that affect HDL-C levels may contribute to exceptional longevity, and they extend such findings to a healthy aging phenotype and to a Japanese population.

Importantly, more work needs to be done in this area because the influence of HDL-C on mortality has not been clearly established for very old persons. For example, a population-based study of 997 elderly (average age 79 years) men and women from Connecticut found that risk factor-adjusted HDL-C levels were not associated with CHD-related mortality (23). However, a follow-up to this report included the same participants in a much larger collaborative study of 3904 elderly men and women of similar age, and found that low HDL-C levels predicted CHD mortality in both sexes, suggesting that the prior study may have lacked sufficient power (22). A 10-year longitudinal study of 350 elderly (75- to 80-year-old), primarily Caucasian men and women from New York found that low HDL-C levels were significantly associated with all-cause mortality in men, but not women (25), and an 11-year study that followed 1211 Chinese retirees (92% men) from average age 70 to average age 80 years found that CHD-related deaths decreased with increasing HDL-C levels (24).

The current long-term follow-up study provides further evidence for an inverse relationship between HDL-C and CVD mortality in one of the largest studies (n = 3562) of oldest-old men (average age 84 years at study's end and maximum age 99 years). In addition, this study provides evidence that higher levels of HDL-C promote a healthy aging advantage for elderly men. Healthy survival as a phenotype (absence of six major age-related diseases with concomitant high physical and cognitive function) has never been studied with regard to HDL-C and CETP gene variants, so this is important and novel information. We found that Japanese-American men of the HHP with the relatively rare Int 14A mutation in the CETP gene were significantly more likely to be healthy beyond 90 years of age. Additionally, a large difference in mortality (reduced by half) between participants with and without the Int 14A mutation suggests an overall survival advantage for men with this variant; however, this trend was not statistically significant. Like other studies of CETP mutations in this group (10,12), the relatively small number of study participants with mutations in the CETP gene and the limited number of CVD events resulted in lack of statistical power, thus making it difficult to detect an association between specific CETP genetic variants and longevity.

Among the advantages of this study are its large number of participants, its longitudinal design, strong phenotyping, and a relatively homogeneous population. The HHP/HAAS is among the most comprehensive and largest studies of aging men and thus provides a valuable opportunity to assess aging- and longevity-related phenotypes and genotypes.

Disadvantages, as mentioned, include the small numbers of participants with one or more copies of the CETP gene variants of interest and limited statistical power. There is also the possibility that the protective effect for healthy aging is a false-positive finding. It should be replicated in other population samples. Another drawback if the finding is confirmed in other populations is that the mechanism may not necessarily be due to the blood level of CETP. Further work should attempt to correlate blood levels of CETP to healthy aging. Many such genetic findings may be population specific. For example, the gene variants that we studied are prevalent in 2%–7% the Japanese population (11) but are rare in other populations. Finally, another limitation of this study is that we are studying elderly individuals who have already survived, and survival factors may differ at younger ages.

The role of CETP as a "longevity gene" (a gene that enhances survival to exceptional old age), has also been called into question, and this area clearly requires further study. On the supportive side, a CETP deficiency mutation (I405V) that causes an increase in HDL concentration and larger particle size has been associated with increased odds for exceptional longevity and decreased odds for dementia in studies of Ashkenazi Jewish centenarians and their offspring (4,5). Some long-lived families in Japan also appear to possess a higher prevalence of the Int 14A variant (26), which has similar effects on HDL levels and particle size as the I405V variant. Furthermore, a study of several hundred frail, community-dwelling octogenarians and nonagenarians in Italy also found a protective effect of HDL-C on the risk of all-cause mortality, although the genetic basis of this was not reported (27). These findings suggest that some aspect of the high HDL phenotype may have lifelong protective effects and that this is apparent in multiple ethnic groups. However, until the current study, whether this phenotype is associated with good health in long-lived persons or "healthy aging" (i.e., low morbidity, high physical and cognitive function as a single phenotype) had not been studied.

On the negative side, the epidemiologic data are not universally supportive. For example, prior cross-sectional studies of Japanese and Italian centenarians found that CETP mutations were not associated with exceptional longevity (28,29), and a marked reduction in the prevalence of the Int 14A mutation was found in a small (n = 67) sample of elderly (>80 years) Japanese participants in comparison with younger participants suggesting increased mortality risk with the variant (30). One cross-sectional study of the HHP cohort reported an excess of CHD in individuals with both a CETP mutation and moderate levels of HDL-C (10), which was contrary to expectations. However, cross-sectional studies are open to survival bias among prevalent cases and caution must be applied when interpreting their results. For example, a more recent longitudinal study of the HHP could not confirm those findings, and instead reported a trend for lower CHD incidence rates in men with a CETP mutation (12).

The epidemiological promise of CETP inhibition for increasing HDL levels and lowering CVD risk has been deemed sufficient enough to initiate clinical trials, but, surprisingly, a recent clinical trial of a promising CETP inhibitor that markedly increases HDL-C (>50%) was terminated due to increased mortality (9). The reasons are unknown, but one possibility is that findings may have been due to higher BP in the intervention group and may have little to do with CETP. However, it raises the important issue of assessing multiple age-related end points, including all-cause mortality.

Despite these hypothetical explanations for the contradictory findings, the reasons for such conflicting results are perplexing. It is possible that the focus on CETP inhibition leading to higher total plasma HDL levels and larger HDL particle size, the two most commonly touted protective mechanisms, may be overly simplistic. Recent work suggests that CETP inhibition does more than just raise HDL or alter HDL particle size. CETP also plays an important role as a modulator of HDL metabolism and affects its composition and properties (31). That is, CETP can alter the distribution and apolipoprotein make-up of HDL particles. Gene variants, such as I405V or Int 14A, which cause CETP deficiency, may cause the apoA-I in these particles to associate with apoA-II and other HDL apolipoproteins (except apoA-IV) forming HDL that differs in apolipoprotein composition and function.

Interestingly, some work suggests that heterozygous CETP-deficient patients, who have highly differentiated HDL, especially those with high LpA-I -1 levels, have more effective reverse cholesterol transport (improved anti-atherogenesis) as compared to homozygotes, who may have very large, undifferentiated HDL particles. Thus CETP heterozygotes may have more effective reverse cholesterol transport and may be at less CVD risk than homozygotes, and we speculate that this might be linked to other phenotypes of healthy aging (32). Therefore, it is plausible that differences in HDL subtype and effectiveness may be one possible explanation for the differential risk seen with different CETP inhibitors and genotypes in clinical and epidemiological studies. These differences might also affect healthy aging and longevity. More research is required in this important area to understand these complexities and to generalize findings between populations.

Conclusion
The current study adds further epidemiologic support for a role of HDL-C and CETP genotype in an ethnic Japanese population for phenotypes related to healthy aging and longevity. Importantly, this study is one of the largest studies on HDL-C and CETP gene variants in older men and one of the few in a minority U.S. population. The findings add further credence that high HDL-C levels may protect against CVD-related mortality and may influence other health-related outcomes important to healthy aging. We speculate that this may be mediated, in part, through deficiency mutations in the CETP gene. These findings, when juxtaposed with recent demonstrations of adverse pharmaceutical effects of the potent CETP inhibitor torcetrapib, indicate that further studies of this important clinical area are warranted to understand mechanisms and potential health outcomes linked to CETP genotype, CETP inhibition, and HDL-C metabolism.

	Acknowledgments

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This research was supported by National Institute of Health grants R01 AG18715-01 to J. D. Curb and R01 AG027060-01 to B. J. Willcox.

	Footnotes

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Decision Editor: Luigi Ferrucci, MD, PhD

Received July 18, 2007

Accepted May 15, 2008

	References

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