J. Lipid Res. Neurobiology of Lipids (ISSN1683-5506)
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Originally published In Press as doi:10.1194/jlr.M300520-JLR200 on February 16, 2004

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
M300520-JLR200v1
45/5/948    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Curb, J. D.
Right arrow Articles by Tall, A. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Curb, J. D.
Right arrow Articles by Tall, A. R.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

Journal of Lipid Research, Vol. 45, 948-953, May 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

A prospective study of HDL-C and cholesteryl ester transfer protein gene mutations and the risk of coronary heart disease in the elderly

J. D. Curb1,*,{dagger},§, R. D. Abbott*,**, B. L. Rodriguez*,{dagger},§, K. Masaki*,{dagger},§, R. Chen*, D. S. Sharp{dagger}{dagger} and A. R. Tall§§

* Pacific Health Research Institute, Honolulu, HI
{dagger} Honolulu Heart Program, Kuakini Medical Center, Honolulu, HI
§ John A. Burns School of Medicine, Departments of Health Science and Epidemiology, Geriatric Medicine, and Medicine, University of Hawaii at Manoa, Honolulu, HI
** Division of Biostatistics and Epidemiology, University of Virginia School of Medicine, Charlottesville, VA
{dagger}{dagger} National Institute for Occupational Safety and Health, Health Effects Laboratory Division, Morgantown, WV
§§ Columbia University, New York, NY

Published, JLR Papers in Press, February 16, 2004. DOI 10.1194/jlr.M300520-JLR200

1 To whom correspondence should be addressed. e-mail: jdcurb{at}phrihawaii.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
High density lipoprotein cholesterol (HDL-C) levels are inversely associated with the incidence of coronary heart disease (CHD) in middle-aged individuals; in the elderly, the association is less clear. Genetic factors, including variations in the cholesteryl ester transfer protein (CETP) gene, play a role in determining HDL-C levels. Controversy remains about whether CETP deficiency and the resultant rise in HDL-C are antiatherogenic, or whether CETP has the opposite effect due to its role in reverse cholesterol transport. In a seven-year follow-up of 2,340 men aged 71–93 in the Honolulu Heart Program, the age-adjusted CHD incidence rates were significantly lower in men with high versus low HDL-C levels. After adjustment for age, hypertension, smoking, and total cholesterol, the relative risk of CHD for those with HDL-C levels >=60 mg/dl, compared with those with HDL-C levels <40 mg/dl, was 0.6. Men with a CETP mutation had the lowest rates of CHD, although this was not statistically significant.

These data indicate that HDL-C remains an important risk factor for CHD in the elderly. Whether a CETP mutation offers additional protection against CHD warrants further investigation.

Abbreviations: BMI, body mass index; CETP, cholesteryl ester transfer protein; CHD, coronary heart disease; CVD, cardiovascular disease; HDL-C, high density lipoprotein cholesterol; HHP, Honolulu Heart Program; LDL-C, low density lipoprotein cholesterol; MI, myocardial infarction

Supplementary key words epidemiology • risk factors • high density lipoprotein cholesterol


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
High density lipoprotein cholesterol (HDL-C) blood levels have been inversely associated with the incidence of coronary heart disease (CHD) in middle-aged and, to a lesser extent, in elderly individuals (1–9). Reports from the Honolulu Heart Program (HHP) were among the first to describe the inverse relationship of "{alpha}" cholesterol (HDL-C) with CHD (10). This inverse HDL-C to CHD relationship in the Honolulu Japanese-American sample has also appeared in four other cohorts (Albany, Framingham, Evans County, and San Francisco) in the Cooperative Lipoprotein Phenotyping Study (1).

The relationships of HDL-C to cardiovascular events in older individuals have been far less consistent than the strong relationships seen in middle-aged individuals. There have been few studies in elderly minority populations. Most studies in older individuals have been case control studies. In addition, few have been able to reliably exclude prevalent atherosclerotic disease.

The mechanistic relationships of the association between HDL-C and CHD remain poorly understood. A number of antiatherogenic properties of HDL-C have been suggested as possible explanations for the association between HDL-C and CHD (11, 12). Genetic factors, including variations in the cholesteryl ester transfer protein (CETP) gene, are thought to play a major role in the determination HDL-C levels. CETP mediates the transfer of cholesteryl esters from HDL-C and low density lipoprotein cholesterol (LDL-C) into triglyceride (TG)-rich lipoproteins (11). Controversy remains about whether CETP deficiency and the resultant rise in HDL-C is antiatherogenic, or whether CETP has the opposite effect due to its role in reverse cholesterol transport. This determination has become important because of the development of pharmaceutical compounds that can alter CETP levels in the body.

We have previously shown in elderly Japanese-American men of the HHP that the prevalence of CETP mutations is high and often associated with elevated concentrations of HDL-C (13). The continued follow-up of the now elderly HHP cohort, and the careful classification of cardiovascular events in this cohort, provide an opportunity to further examine the relationship of HDL-C and CETP mutations to incident CHD.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
The HHP is a long-term, prospective study of heart disease, stroke, and other diseases in a sample of 8,006 Japanese-American men, aged 45 to 68 years at the time of study enrollment in 1965–1968. Kuakini Medical Center's Institutional Review Board approved the project. Follow-up in this report began at physical examinations given from 1991–1993 to 3,741 surviving HHP subjects. Men with a history of CHD at this examination, and those who reported being on lipid lowering medications, were excluded from these analyses. Prevalent cases of stroke and cancer were also excluded.

In this report, up to 7 years of follow-up data are available to examine the relationship between HDL-C and CHD. Based on a comprehensive system of follow-up, cases of CHD were identified by continuous surveillance of hospital discharge records, obituary notices, and death certificates. Using a standardized protocol and case definition criteria, a physician committee classified suspected endpoints. For this report, subjects were followed for the first occurrence of CHD. Here, CHD is defined to include unequivocal findings of a nonfatal myocardial infarction (MI), coronary death, and sudden death within an hour that could not be attributed to another cause. Risk factor measurements included body mass index (BMI) (kg/m2), physical activity index, alcohol consumption, hypertension, serum cholesterol, smoking habits, serum glucose levels, and TG levels. A diagnosis of hypertension was made when either a systolic or diastolic blood pressure was >=160 and 95 mm Hg, respectively, or when a subject was receiving medication for high blood pressure. Assessment of physical activity was based on the use of the physical activity index, a common measure used to quantify overall metabolic output in a typical 24-h period and known to be inversely associated with the risk of cardiovascular disease (CVD) (14). The methods and procedures utilized in the HHP are documented in detail elsewhere (15, 16).

Laboratory analyses
Blood was centrifuged within 30 min of collection at 3,000 g for 10 min at 4°C, and the plasma was frozen at –70°C for up to 2 months. Samples were then shipped on dry ice to the University of Vermont, where HDL-C was separated by precipitation with dextran sulfate and magnesium chloride (17). DNA was obtained from white blood cells separated from plasma samples procured at the examination, and genotyping was carried out for intron 14 and exon 15 mutations in the CETP gene. For this report, a CETP mutation is defined as the presence of either an intron 14 or an exon 15 mutation.

Statistical methods
The percent of men who fell within a range of HDL-C and who had a CETP mutation, were calculated within age-specific strata for ages that were observed at the time of study enrollment. Age-adjusted risk factors across the ranges of HDL-C levels and according to CETP status were estimated from analysis of covariance models (18). Similar procedures were used to assess changing levels of HDL-C and the percent of men with a CETP mutation as they might occur with age (a test for trend). Age-adjusted tests further examined trends in risk factor changes across levels of HDL-C.

Crude and age-adjusted incidence rates of CHD in person-years were estimated according to ranges of HDL-C concentrations and by CETP mutation status based on the 7 years of follow-up data that were available for the 2,340 men without prevalent disease, who were examined from 1991 to 1993 (18). To test for an independent effect of HDL-C level and CETP mutation on the risk of CHD after adjusting for age and the other covariates, proportional hazard regression models were used (19). While HDL-C was modeled as a continuous risk factor, relative risks of CHD (and associated confidence intervals) were also estimated comparing the risk of CHD between the ranges of HDL-C levels. When treated as a continuous variable, a test for trend was provided for whether there was a change in the risk of CHD with changes in levels of HDL-C. Similar models were used to compare the incidence of CHD between men with and without a CETP mutation. All reported P values were based on two-sided tests of significance. Clinically significant cut points based on the National Cholesterol Education Program guidelines were used to examine the relationship of HDL-C to age and age-adjusted risk factors (20).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Shown in Table 1 are the percent of HHP men whose HDL-C levels fell in three clinically important categories (<40, 40–59, and >=60 mg/dl), and who were characterized with either of the two CETP mutations, by 5-year age group. As can be seen, 23.6% of the men had HDL-C levels of >=60 mg/dl. Prevalence of HDL-C values of >=60 mg/dl increased significantly with age. There was no indication of a relationship between CETP mutations and age.


View this table:
[in this window]
[in a new window]
  		TABLE 1. Percent of men within ranges of HDL-C levels and the percent prevalence of CETP mutation according to age

 
Shown in Table 2 are the age-adjusted baseline characteristics of the study participants by HDL-C category. Significant positive associations between HDL-C levels and physical activity index, alcohol intake, and serum cholesterol were seen. In contrast, BMI, the prevalence of hypertension, serum glucose, and TGs declined with increasing levels of HDL-C. Rising HDL-C was also associated with a significant increase in the prevalence of CETP mutations. Prevalence of CETP mutations was more than doubled in men with HDL-C levels >=60 mg/dl versus men with levels <40 mg/dl.


View this table:
[in this window]
[in a new window]
  		TABLE 2. Age-adjusted percents and mean risk factor levels by ranges of HDL-C levels

 
Table 3 shows age-adjusted characteristics for those with and without CETP mutations. There were 118 individuals with either mutation. Eleven were heterozygous for intron 14, 106 were heterozygotes for exon 15, and 1 was homozygote for exon 15. As expected from Table 2, HDL-C levels were significantly higher in those with a CETP mutation. In contrast, TG and glucose levels were lower in those with a mutation. Relationships with the other risk factors were not apparent.


View this table:
[in this window]
[in a new window]
  		TABLE 3. Age-adjusted percents of mean risk factor levels by the presence and absence of a CETP mutation

 
Figure 1 shows the relative risks of CHD (adjusted for age, hypertension, smoking, and total cholesterol) for those with HDL-C levels between 40 mg/dl to 59 mg/dl and >=60 mg/dl, as compared with those with HDL-C levels that were lower (<40 mg/dl). As can be seen, the risk of CHD in men with HDL-C concentrations >=60 mg/dl was nearly halved when compared with men with HDL-C levels <40 mg/dl. Risk of CHD declined significantly with increasing HDL concentration (P < 0.05). The age-adjusted CHD incidence rates declined from 16.1 per 1,000 person years for men with HDL-C levels <40 mg/dl to 9.8 per 1,000 person years in men with HDL-C levels >=60 mg/dl.



View larger version (13K):
[in this window]
[in a new window]
  		Fig. 1. Age factor- and risk factor-adjusted relative risks of coronary heart disease (CHD) for men with high density lipoprotein cholesterol (HDL-C) levels >=60 mg/dl and between 40–59 mg/dl compared with levels below 40 mg/dl. Adjusted risk factors included hypertension, smoking, and cholesterol. *Significantly lower risk as compared to men with an HDL-C level <40 mg/dl (P < 0.05).

 
Shown in Fig. 2 is the age-adjusted CHD incidence rate per 1,000 person years by level of HDL-C and according to the presence and the absence of a CETP mutation. The two lower HDL-C subgroups were combined due to the small number of events in those with a CETP mutation. Among the four groups, the only significant difference in the rates of CHD occurred between the two HDL-C strata in men without a CETP mutation (P < 0.05). Although the presence of a CETP mutation appeared protective, even when HDL-C strata were pooled, the effect of CETP on the risk of CHD failed to reach statistical significance. As noted earlier, however, the number of individuals with a mutation is small (118), and, among this group, there were only seven events. Thus, the power to detect an association between CETP and the future risk of CHD is limited. It may be that with a larger sample size, a significant relationship between CETP and CHD would have emerged, including a possible interaction effect between CETP and HDL-C.



View larger version (13K):
[in this window]
[in a new window]
  		Fig. 2. Age-adjusted incidence of CHD according to ranges of HDL-C and in the absence and the presence of a cholesteryl ester transfer protein (CETP) mutation. *Number of CHD events/men at risk. **Significantly lower risk compared to men with HDL-C <60 mg/dl and without a CETP mutation (P < 0.05).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
An important finding of this study is that HDL-C is a significant risk factor for CHD in this elderly sample. The importance of HDL-C as a risk factor for CHD in those over 70 years-of-age has not been consistently demonstrated (8, 9, 21–23). In contrast, low levels of HDL-C have been independently and strongly associated with an increased risk of coronary artery disease in numerous studies involving middle-aged cohorts (1–7). For example, the Framingham Heart Study found that men aged 50 years to 79 years with HDL-C levels in the bottom quartile had a 60% to 70% excess of MI compared to men with higher HDL-C levels. Effects were even greater in women (2). Combined results from four large observational studies indicated that a 1 mg/dl increment in HDL-C was associated with approximately a 2% to 3% decrease in the risk of coronary artery disease in middle-aged individuals (3). The relationship between HDL-C and CHD is not confined to Caucasians. In middle-aged men in Japan, the incidence of CHD and MI, adjusted for other risk factors, was 3–4x higher in the lowest quartile of HDL-C than in the highest quartile (7).

In elderly samples, the relationship between HDL-C and CHD appears equivocal. In a population-based sample of 997 men and women over 70 years of age from Connecticut, HDL-C was not associated with CHD mortality or hospitalizations from CVD (22). In contrast, a follow-up of a larger population from three centers (3,904 women and men) found that low HDL-C predicted CHD mortality and the occurrence of new CHD events (8). Both studies also adhered to the same protocol and laboratory techniques with case ascertainment based on death certificates. Unlike the HHP, however, access to and utilization of clinically rigorous methods for detecting and classifying events were not available.

Another principal goal of the present study was to provide prospective information on the relationship between heterozygous CETP gene mutations and CHD. Although not statistically significant, the risk of CHD is lower in the presence versus the absence of a CETP mutation, especially for those individuals with HDL-C levels >=60 mg/dl. This study's findings are similar to an earlier prevalence study reported by Moriyama et al. (24), in which subjects with CETP mutations and HDL-C levels >80 mg/dl were found to have very little CHD.

Our current findings did not confirm an earlier observation of a cross-sectional excess of CHD in subjects with a CETP gene mutation and HDL-C levels ranging from 40 mg/dl to 60 mg/dl (13). The differences in the longitudinal and cross-sectional findings may be partly explained by the exclusion of prevalent cases of CHD, stroke, and cancer in the current longitudinal analysis. Although CETP mutations should not change with age, it may be that the gene mutations have different effects in older individuals. The prospective study design also includes other advantages, which may have contributed to differences from the cross-sectional study. A shortcoming of both studies is the relatively low number of men with a CETP mutation and, therefore, limited statistical power.

Earlier studies in subjects with CETP mutations have indicated a possible susceptibility to CHD. A small number of patients with a CETP mutation, hepatic lipase deficiency, high HDL-C, and multiple risk factors were reported to have an excess of coronary artery disease (25). Moreover, a study in a Japanese community with a high prevalence of the intron 14 mutation found a high rate of ECG changes in subjects with very high HDL-C levels (26). These changes, however, were not specifically related to CETP mutations, and the data could be potentially confounded by other factors such as alcohol intake (27). Studies on CETP gene polymorphisms in European samples have shown associations with HDL-C levels and conflicting data concerning relationships with CHD (27, 28). These polymorphisms appear to have modest and indirect effects on plasma CETP levels.

Animal studies have also provided data on the relationship between CETP and atherogenesis. Studies on the inhibition of CETP in rabbits by several different strategies have indicated an antiatherogenic effect of CETP (29, 30). In particular, a CETP inhibitor drug was highly efficacious in reducing atherosclerosis (29). Other studies in CETP transgenic mice have shown that effects on atherogenesis depend on the metabolic context of CETP expression (31–33).

Therapeutic inhibition of CETP has been suggested as a treatment for elevating HDL-C levels in humans (33, 34), and recent studies indicate that CETP inhibitors can raise HDL-C and lower LDL-C (35). While it is clear that high-level inhibition is effective at raising HDL-C, one cannot predict with certainty the ultimate effects on atherosclerosis. Although this might represent a disruption of reverse cholesterol transport, it is likely that HDL-C and cholesteryl ester clearance in the liver can occur by other mechanisms, including via scavenger receptor B1. The large, apoE-rich HDL-C particles that accumulate in the absence of CETP may have other beneficial properties, such as antioxidant or antiinflammatory effects (36) and may compete with atherogenic lipoproteins for retention on the arterial matrix (37). Potential adverse properties of these particles have been suggested by others (38, 39).

In summary, these data indicate that HDL-C remains an important risk factor for CHD in the elderly. This important relationship is seen here in a prospective cohort study with rigid quality control and detailed and clinically rigorous endpoint ascertainment and classification. Inasmuch as many of the classic risk factors have altered relationships with cardiovascular endpoints in the elderly, HDL-C may prove to be an increasingly useful clinical tool for identifying high-risk individuals in this age group (40). While definitive conclusions are not possible, the results are also suggestive of a lower rate of coronary events in those with a CETP mutation and a high HDL-C. Though the present study is consistent with the idea that therapeutic inhibition could be beneficial for CHD, more data are needed to determine whether CETP mutation significantly reduces the risk of CHD.


   ACKNOWLEDGMENTS
 
This work was supported by National Institutes of Health Grants NO1-HC-05102 and UO1-HL-56274 (The Honolulu Heart Program) and ROI HL-56984 (SCOR) (A.T.).

Manuscript received December 19, 2003 and in revised form February 6, 2004.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
  1. Castelli, W. P., J. T. Doyle, T. Gordon, C. G. Hames, M. C. Hjortland, S. B. Hulley, A. Kagan, and W. J. Zukel. 1977. HDL cholesterol and other lipids in coronary heart disease. The cooperative lipoprotein phenotyping study. Circulation. 55: 767–772.[Abstract/Free Full Text]

  2. Abbott, R. D., P. W. Wilson, W. B. Kannel, and W. P. Castelli. 1988. High density lipoprotein cholesterol, total cholesterol screening, and myocardial infarction. The Framingham Study. Arteriosclerosis. 8: 207–211.[Abstract/Free Full Text]

  3. Gordon, D. J., and B. M. Rifkind. 1989. High-density lipoprotein—the clinical implications of recent studies. N. Engl. J. Med. 321: 1311–1316.[Medline]

  4. Stampfer, M. J., F. M. Sacks, S. Salvini, W. C. Willett, and C. H. Hennekens. 1991. A prospective study of cholesterol, apolipoproteins, and the risk of myocardial infarction. N. Engl. J. Med. 325: 373–381.[Abstract]

  5. Pekkanen, J., S. Linn, G. Heiss, C. M. Suchindran, A. Leon, B. M. Rifkind, and H. A. Tyroler. 1990. Ten-year mortality from cardiovascular disease in relation to cholesterol level among men with and without preexisting cardiovascular disease. N. Engl. J. Med. 322: 1700–1707.[Abstract]

  6. Assmann, G., H. Schulte, A. von Eckardstein, and Y. Huang. 1996. High-density lipoprotein cholesterol as a predictor of coronary heart disease risk. The PROCAM experience and pathophysiological implications for reverse cholesterol transport. Atherosclerosis. 124 (Suppl.): S11–S20.

  7. Kitamura, A., H. Iso, Y. Naito, M. Iida, M. Konishi, A. R. Folsom, S. Sato, M. Kiyama, M. Nakamura, and T. Sankai. 1994. High-density lipoprotein cholesterol and premature coronary heart disease in urban Japanese men. Circulation. 89: 2533–2539.[Abstract/Free Full Text]

  8. Corti, M. C., J. M. Guralnik, M. E. Salive, T. Harris, T. S. Field, R. B. Wallace, L. F. Berkman, T. E. Seeman, R. J. Glynn, and C. H. Hennekens. 1995. HDL cholesterol predicts coronary heart disease mortality in older persons. JAMA. 274: 539–544.[Abstract]

  9. Zimetbaum, P., W. H. Frishman, W. L. Ooi, M. P. Derman, M. Aronson, L. I. Gidez, and H. A. Eder. 1992. Plasma lipids and lipoproteins and the incidence of cardiovascular disease in the very elderly. The Bronx Aging Study. Arterioscler. Thromb. 12: 416–423.[Abstract/Free Full Text]

  10. Rhoads, G. G., C. L. Gulbrandsen, and A. Kagan. 1976. Serum lipoproteins and coronary heart disease in a population study of Hawaii Japanese men. N. Engl. J. Med. 294: 293–298.[Abstract]

  11. Lusis, A. J. 2000. Atherosclerosis. Nature. 407: 233–241.[CrossRef][Medline]

  12. Tall, A. R. 1990. Plasma high density lipoproteins. Metabolism and relationship to atherogenesis. J. Clin. Invest. 86: 379–384.

  13. Zhong, S., D. S. Sharp, J. S. Grove, C. Bruce, K. Yano, J. D. Curb, and A. R. Tall. 1996. Increased coronary heart disease in Japanese-American men with mutation in the cholesteryl ester transfer protein gene despite increased HDL levels. J. Clin. Invest. 97: 2917–2923.[Medline]

  14. Abbott, R. D., B. L. Rodriguez, C. M. Burchfiel, and J. D. Curb. 1994. Physical activity in older middle-aged men and reduced risk of stroke: the Honolulu Heart Program. Am. J. Epidemiol. 139: 881–893.[Abstract/Free Full Text]

  15. Kagan, A., B. R. Harris, W. Winkelstein, Jr., K. G. Johnson, H. Kato, S. L. Syme, G. G. Rhoads, M. L. Gay, M. Z. Nichaman, H. B. Hamilton, and J. Tillotson. 1974. Epidemiologic studies of coronary heart disease and stroke in Japanese men living in Japan, Hawaii and California: demographic, physical, dietary and biochemical characteristics. J. Chronic Dis. 27: 345–364.[CrossRef][Medline]

  16. Worth, R. M., and A. Kagan. 1970. Ascertainment of men of Japanese ancestry in Hawaii through World War II Selective Service registration. J. Chronic Dis. 23: 389–397.[CrossRef][Medline]

  17. Fried, L. P., N. O. Borhani, P. Enright, C. D. Furberg, J. M. Gardin, R. A. Kronmal, L. H. Kuller, T. A. Manolio, M. B. Mittelmark, and A. Newman. 1991. The Cardiovascular Health Study: design and rationale. Ann. Epidemiol. 1: 263–276.[Medline]

  18. Lane, P. W., and J. A. Nelder. 1982. Analysis of covariance and standardization as instances of prediction. Biometrics. 38: 613–621.[CrossRef][Medline]

  19. Cox, D. R. 1972. Regression models and life tables. J. Roy. Stat. Soc. 34: 187–202.

  20. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. 2001. Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA. 285: 2486–2497.[Free Full Text]

  21. Reed, D., and R. Benfante. 1992. Lipid and lipoprotein predictors of coronary heart disease in elderly men in the Honolulu Heart Program. Ann. Epidemiol. 2: 29–34.[Medline]

  22. Krumholz, H. M., T. E. Seeman, S. S. Merrill, C. F. Mendes de Leon, V. Vaccarino, D. I. Silverman, R. Tsukahara, A. M. Ostfeld, and L. F. Berkman. 1994. Lack of association between cholesterol and coronary heart disease mortality and morbidity and all-cause mortality in persons older than 70 years. JAMA. 272: 1335–1340.[Abstract]

  23. Barrett-Connor, E. 1992. Hypercholesterolemia predicts early death from coronary heart disease in elderly men but not women. The Rancho Bernardo Study. Ann. Epidemiol. 2: 77–83.[Medline]

  24. Moriyama, Y., T. Okamura, A. Inazu, M. Doi, H. Iso, Y. Mouri, Y. Ishikawa, H. Suzuki, M. Iida, J. Koizumi, H. Mabuchi, and Y. Komachi. 1998. A low prevalence of coronary heart disease among subjects with increased high-density lipoprotein cholesterol levels, including those with plasma cholesteryl ester transfer protein deficiency. Prev. Med. 27: 659–667.[CrossRef][Medline]

  25. Hirano, K., S. Yamashita, Y. Kuga, N. Sakai, S. Nozaki, S. Kihara, T. Arai, K. Yanagi, S. Takami, and M. Menju. 1995. Atherosclerotic disease in marked hyperalphalipoproteinemia. Combined reduction of cholesteryl ester transfer protein and hepatic triglyceride lipase. Arterioscler. Thromb. Vasc. Biol. 15: 1849–1856.[Abstract/Free Full Text]

  26. Hirano, K., S. Yamashita, N. Nakajima, T. Arai, T. Maruyama, Y. Yoshida, M. Ishigami, N. Sakai, K. Kameda-Takemura, and Y. Matsuzawa. 1997. Genetic cholesteryl ester transfer protein deficiency is extremely frequent in the Omagari area of Japan. Marked hyperalphalipoproteinemia caused by CETP gene mutation is not associated with longevity. Aterioscler. Thromb. Vasc. Biol. 17: 1053–1059.[Abstract/Free Full Text]

  27. Fumeron, F., D. Betoulle, G. Luc, I. Behague, S. Ricard, O. Poirier, R. Jemaa, A. Evans, D. Arveiler, and P. Marques-Vidal. 1995. Alcohol intake modulates the effect of a polymorphism of the cholesteryl ester transfer protein gene on plasma high density lipoprotein and the risk of myocardial infarction. J. Clin. Invest. 96: 1664–1671.

  28. Agerholm-Larsen, B., A. Tybjaerg-Hansen, P. Schnohr, R. Steffensen, and B. G. Nordestgaard. 2000. Common cholesteryl ester transfer protein mutations, decreased HDL cholesterol, and possible decreased risk of ischemic heart disease: The Copenhagen City Heart Study. Circulation. 102: 2197–2203.[Abstract/Free Full Text]

  29. Okamoto, H., F. Yonemori, K. Wakitani, T. Minowa, K. Maeda, and H. Shinkai. 2000. A cholesteryl ester transfer protein inhibitor attenuates atherosclerosis in rabbits. Nature. 406: 203–207.[CrossRef][Medline]

  30. Yamada, N., H. Shimano, and Y. Yazaki. 1995. Role of apolipoprotein E in lipoprotein metabolism and in the process of atherosclerosis. J. Atheroscler. Thromb. 2 (Suppl.): S29–S33.

  31. Hayek, T., L. Masucci-Magoulas, X. Jiang, A. Walsh, E. Rubin, J. L. Breslow, and A. R. Tall. 1995. Decreased early atherosclerotic lesions in hypertriglyceridemic mice expressing cholesteryl ester transfer protein transgene. J. Clin. Invest. 96: 2071–2074.

  32. Masucci-Magoulas, L., I. J. Goldberg, C. L. Bisgaier, H. Serajuddin, O. L. Francone, J. L. Breslow, and A. R. Tall. 1997. A mouse model with features of familial combined hyperlipidemia. Science. 275: 391–394.[Abstract/Free Full Text]

  33. Bruce, C., R. A. Chouinard, Jr., and A. R. Tall. 1998. Plasma lipid transfer proteins, high-density lipoproteins, and reverse cholesterol transport. Annu. Rev. Nutr. 18: 297–330.[CrossRef][Medline]

  34. Brown, M. L., A. Inazu, C. B. Hesler, L. B. Agellon, C. Mann, M. E. Whitlock, Y. L. Marcel, R. W. Milne, J. Koizumi, and H. Mabuchi. 1989. Molecular basis of lipid transfer protein deficiency in a family with increased high-density lipoproteins. Nature. 342: 448–451.[CrossRef][Medline]

  35. de Grooth, G. J., J. A. Kuivenhoven, A. F. Stalenhoef, J. de Graaf, A. H. Zwinderman, J. L. Posma, A. van Tol, and J. J. Kastelein. 2002. Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: a randomized phase II dose-response study. Circulation. 105: 2159–2165.[Abstract/Free Full Text]

  36. Parthasarathy, S., J. Barnett, and L. G. Fong. 1990. High-density lipoprotein inhibits the oxidative modification of low-density lipoprotein. Biochim. Biophys. Acta. 1044: 275–283.[Medline]

  37. Saxena, U., E. Ferguson, and C. L. Bisgaier. 1993. Apolipoprotein E modulates low density lipoprotein retention by lipoprotein lipase anchored to the subendothelial matrix. J. Biol. Chem. 268: 14812–14819.[Abstract/Free Full Text]

  38. Ishigami, M., S. Yamashita, N. Sakai, T. Arai, K. Hirano, H. Hiraoka, K. Kameda-Takemura, and Y. Matsuzawa. 1994. Large and cholesteryl ester-rich high-density lipoproteins in cholesteryl ester transfer protein (CETP) deficiency cannot protect macrophages from cholesterol accumulation induced by acetylated low-density lipoproteins. J. Biochem. (Tokyo). 116: 257–262.[Abstract/Free Full Text]

  39. Hannuksela, M. L., M. E. Brousseau, S. M. Meyn, H. Nazih, G. Bader, R. D. Shamburek, P. Alaupovic, and H. B. Brewer, Jr. 2002. In vivo metabolism of apolipoprotein E within the HDL subpopulations LpE, LpE:A-I, LpE:A-II and LpE:A-I:A-II. Atherosclerosis. 165: 205–220.[CrossRef][Medline]

  40. Schatz, I. J., K. Masaki, K. Yano, R. Chen, B. L. Rodriguez, and J. D. Curb. 2001. Cholesterol and all-cause mortality in elderly people from the Honolulu Heart Program: a cohort study. Lancet. 358: 351–355.[CrossRef][Medline]


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:


Home page
 JAMAHome page
A. Thompson, E. Di Angelantonio, N. Sarwar, S. Erqou, D. Saleheen, R. P. F. Dullaart, B. Keavney, Z. Ye, and J. Danesh
Association of Cholesteryl Ester Transfer Protein Genotypes With CETP Mass and Activity, Lipid Levels, and Coronary Risk
JAMA, June 18, 2008; 299(23): 2777 - 2788.
[Abstract] [Full Text] [PDF]

Home page
 NEJMHome page
K. J. Lackner, L. J. Cohn, R. P. Dullaart, A. C. M. Kobold, A. van Tol, P. Barter, C. L. Shear, J. H. Revkin, and D. J. Rader
Torcetrapib and Coronary Events
N. Engl. J. Med., April 24, 2008; 358(17): 1862 - 1864.
[Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
M. Zeller, D. Masson, M. Farnier, L. Lorgis, V. Deckert, J.-P. Pais de Barros, C. Desrumaux, P. Sicard, J. Grober, D. Blache, et al.
High Serum Cholesteryl Ester Transfer Rates and Small High-Density Lipoproteins Are Associated With Young Age in Patients With Acute Myocardial Infarction
J. Am. Coll. Cardiol., November 13, 2007; 50(20): 1948 - 1955.
[Abstract] [Full Text] [PDF]

Home page
 NEJMHome page
P. Barter, A. M. Gotto, J. C. LaRosa, J. Maroni, M. Szarek, S. M. Grundy, J. J.P. Kastelein, V. Bittner, J.-C. Fruchart, and the Treating to New Targets Investigators
HDL Cholesterol, Very Low Levels of LDL Cholesterol, and Cardiovascular Events
N. Engl. J. Med., September 27, 2007; 357(13): 1301 - 1310.
[Abstract] [Full Text] [PDF]

Home page
 JAMAHome page
I. M. Singh, M. H. Shishehbor, and B. J. Ansell
High-Density Lipoprotein as a Therapeutic Target: A Systematic Review
JAMA, August 15, 2007; 298(7): 786 - 798.
[Abstract] [Full Text] [PDF]

Home page
 Arch Intern MedHome page
C. B. Schechter
Longevity and Cardiovascular Disease: Context and Overview
Arch Intern Med, March 12, 2007; 167(5): 428 - 429.
[Full Text] [PDF]

Home page
 J. Lipid Res.Home page
J. F. Thompson, L. S. Wood, E. H. Pickering, B. DeChairo, and C. L. Hyde
High-density genotyping and functional SNP localization in the CETP gene
J. Lipid Res., February 1, 2007; 48(2): 434 - 443.
[Abstract] [Full Text] [PDF]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
A. R. Tall, L. Yvan-Charvet, and N. Wang
The Failure of Torcetrapib: Was it the Molecule or the Mechanism?
Arterioscler. Thromb. Vasc. Biol., February 1, 2007; 27(2): 257 - 260.
[Full Text] [PDF]

Home page
 Eur Heart JHome page
P. K. Shah
Inhibition of CETP as a novel therapeutic strategy for reducing the risk of atherosclerotic disease
Eur. Heart J., January 1, 2007; 28(1): 5 - 12.
[Abstract] [Full Text] [PDF]

Home page
 NeurologyHome page
N. Barzilai, G. Atzmon, C. A. Derby, J. M. Bauman, and R. B. Lipton
A genotype of exceptional longevity is associated with preservation of cognitive function
Neurology, December 26, 2006; 67(12): 2170 - 2175.
[Abstract] [Full Text] [PDF]

Home page
 J. Gerontol. A Biol. Sci. Med. Sci.Home page
G. Florvall, S. Basu, and A. Larsson
Apolipoprotein A1 Is a Stronger Prognostic Marker Than Are HDL and LDL Cholesterol for Cardiovascular Disease and Mortality in Elderly Men
J. Gerontol. A Biol. Sci. Med. Sci., December 1, 2006; 61(12): 1262 - 1266.
[Abstract] [Full Text] [PDF]

Home page
 Pharmacol. Rev.Home page
A. Kontush and M. J. Chapman
Functionally Defective High-Density Lipoprotein: A New Therapeutic Target at the Crossroads of Dyslipidemia, Inflammation, and Atherosclerosis
Pharmacol. Rev., September 1, 2006; 58(3): 342 - 374.
[Abstract] [Full Text] [PDF]

Home page
 J. Gerontol. A Biol. Sci. Med. Sci.Home page
B. J. Willcox, D. C. Willcox, Q. He, J. D. Curb, and M. Suzuki
Siblings of okinawan centenarians share lifelong mortality advantages.
J. Gerontol. A Biol. Sci. Med. Sci., April 1, 2006; 61(4): 345 - 354.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
P. J. Barter and J. J.P. Kastelein
Targeting Cholesteryl Ester Transfer Protein for the Prevention and Management of Cardiovascular Disease
J. Am. Coll. Cardiol., February 7, 2006; 47(3): 492 - 499.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
C. J. Packard, I. Ford, M. Robertson, J. Shepherd, G. J. Blauw, M. B. Murphy, E. L.E.M. Bollen, B. M. Buckley, S. M. Cobbe, A. Gaw, et al.
Plasma Lipoproteins and Apolipoproteins as Predictors of Cardiovascular Risk and Treatment Benefit in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER)
Circulation, November 15, 2005; 112(20): 3058 - 3065.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
L. Dumont, T. Gautier, J.-P. P. de Barros, H. Laplanche, D. Blache, P. Ducoroy, J. Fruchart, J.-C. Fruchart, P. Gambert, D. Masson, et al.
Molecular Mechanism of the Blockade of Plasma Cholesteryl Ester Transfer Protein by Its Physiological Inhibitor Apolipoprotein CI
J. Biol. Chem., November 11, 2005; 280(45): 38108 - 38116.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
M. L. Wolfe and D. J. Rader
Cholesteryl Ester Transfer Protein and Coronary Artery Disease: An Observation With Therapeutic Implications
Circulation, September 14, 2004; 110(11): 1338 - 1340.
[Full Text] [PDF]

Home page
 CirculationHome page
S. M. Boekholdt, J.-A. Kuivenhoven, N. J. Wareham, R. J.G. Peters, J. W. Jukema, R. Luben, S. A. Bingham, N. E. Day, J. J.P. Kastelein, and K.-T. Khaw
Plasma Levels of Cholesteryl Ester Transfer Protein and the Risk of Future Coronary Artery Disease in Apparently Healthy Men and Women: The Prospective EPIC (European Prospective Investigation into Cancer and nutrition)-Norfolk Population Study
Circulation, September 14, 2004; 110(11): 1418 - 1423.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
M300520-JLR200v1
45/5/948    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Curb, J. D.
Right arrow Articles by Tall, A. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Curb, J. D.
Right arrow Articles by Tall, A. R.
Social Bookmarking
Add to CiteULike   Add to Complore