Deficiency of cholesteryl ester transfer protein and gene polymorphisms of lipoprotein lipase and hepatic lipase are not associated with longevity.

Received: 11 September 2002 / Accepted: 8 November 2002 / Published online: 11 February 2003

Springer-Verlag 2003

Abstract

Cholesteryl ester transfer protein (CETP) is one of the key proteins in reverse cholesterol transport (RCT). The role of CETP in atherosclerosis remains controversial. In this study, we investigated the associations between polymorphisms of CETP (mutations in intron 14 and exon 15, and Taq1B), hepatic lipase (C-514T), lipoprotein lipase (PvuII and HindIII), and ATP-binding cassette transporter 1 (R219K) loci and longevity in 256 centenarians and 190 healthy younger controls. Although heterozygous CETP deficiency and the B2 allele of the Taq1B polymorphism were consistently associated with higher HDL-C concentrations both in centenarians and controls, the allelic frequencies of those polymorphisms did not differ between the two groups. The allelic frequencies of other gene polymorphisms in RCT were not different between the two groups. Centenarians with lipoprotein lipase P(/) genotype had significantly higher HDL-C concentration than those with P(/+) or with P(+/+). In contrast, there was no such a relationship among controls. In stepwise multiple regression analysis, serum albumin, CETP deficiency, and lipoprotein lipase PvuII genotype were independently associated with HDL-C in centenarians. Sex, CETP deficiency, and the Taq1B genotype were also independently associated with HDL-C; however, lipoprotein lipase PvuII genotype had no significant effect on their HDL-C in controls. In conclusion, we observed that CETP deficiency and other gene polymorphisms in RCT have no impact on longevity for Japanese centenarians.

YASUMICHI ARAI and NOBUYOSHI HIROSE received their Ph.D. in lipoprotein metabolism of centenarians from the Keio University Graduate School in Tokyo, Japan. YASUMICHI ARAI is presently Assistant Professor of the Department of Geriatric Medicine, Keio University School of Medicine, and a research fellow of the Centenarians Study. His research interest includes interdisciplinary and multidisciplinary approaches to centenarians. NOBUYOSHI HIROSE is presently Assistant Professor of the Department of Geriatric Medicine, Keio University School of Medicine, and a chief investigator of the Tokyo Centenarians Study.

Keywords

Reverse cholesterol transport
Lipoprotein lipase
Cholesteryl ester transfer protein
ABCA1
Centenarian

French [20], Finnish [21], and Japanese centenarians [23, 24, 25]. It is interesting to investigate associations between CETP deficiency and longevity in Japan, where the prevalence of deficiency is extremely high and the life expectancy is longest around the world. It is also worth examining the hypothesis that rather than a defect of risk factor for atherosclerosis, protective factors by nature could be advantageous for longevity. Therefore we have examined the associations of CETP deficiency as well as other genetic polymorphisms involved in RCT and longevity in 256 Japanese centenarians and 190 younger controls.

PCR: Polymerase chain reaction
RCT: Reverse cholesterol transport
RFLP: Restriction fragment length polymorphism

Introduction

High-density lipoprotein cholesterol (HDL-C) has potentially antiatherogenic properties. Numerous epidemiological studies have confirmed that a low level of HDL-C is a strong risk factor for coronary artery disease (CAD) [1]; however, there is evidence that not quantity but underlying mechanisms of high HDL-C levels are important for preventing atherosclerosis [2, 3]. Reverse cholesterol transport (RCT), which enhances cholesterol efflux from the arterial wall and transports it to the liver for reuse or excretion into bile, has been proposed as one of the possible antiatherogenic mechanisms of HDL. Cholesteryl ester transfer protein (CETP) is a carrier protein in RCT, which mediates the transfer of cholesteryl esters from HDL to apolipoprotein (apo) B-containing lipoproteins, thus enhancing RCT. The role of CETP in atherosclerosis remains controversial. Several mutations have been described at the CETP gene locus that cause depletion of CETP activity and consequently high HDL-C in plasma, especially in Japan [4, 5]. It has been demonstrated that CETP deficiency exhibits atherogenicity when combined with serum HDL-C levels lower than 60 mg/dl [6] or with low activity of hepatic lipase [7Corrected Text:

Significantly higher levels of HDL-C (67.12 vs. 53.14 mg/dl, P<0.0001), apoA1 (151.18 vs. 138.17 mg/dl, P=0.0018), and CETP mass (3.91±1.0 vs. 3.50±0.7 g/ml, P=0.014), and lower levels of triglyceride (7646 vs. 13998 mg/dl, P=0.0002 by using logarithmically transformed value), apoB (8020 vs. 9826 mg/dl, P<0.0001), and body mass index (20.5±2.2 vs. 23.6±3.3, P<0.0001) were observed in centenarians as compared to male controls.

Recently, there have been many findings from studies that have extensively investigated the associations between genetic predisposition for fatal disease and longevity [20, 21, 22, 23]. For example, the allele of the apoE gene which is related not only to an increase risk for CAD but also to the development of lipid measurements.

Nonfasting venous blood (20 ml) was collected from all subjects. Plasma was immediately separated by centrifugation at 4°C.