Deficiency of choresteryl 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 con- troversial. In this study we investigated the associations between polymorphisms of CETP (mutations in intron 14 and exon 15, and Taq1B), hepatic lipase (C-514T), li- poprotein 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 was 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 fre- quencies of other gene polymorphisms in RCT were not different between the two groups. Centenarians with li- − − poprotein 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 con- clusion, we observed that CETP deficiency and other gene polymorphisms in RCT have no impact on longevi- ty for Japanese centenarians.

YASUMICHI ARAI NOBUYOSHI HIROSE received his Ph.D. in lipopro- is presently Assistant Profes- tein metabolism of centenari- sor of the Department of Geri- ans from the Keio University atric Medicine, Keio Universi- Graduate School in Tokyo, ty School of Medicine, and a Japan. He is presently chief investigator of the Tokyo a research fellow of the Centenarians Study. His Department of Geriatric research interest includes in- Medicine, Keio University terdisciplinary and multidisci- School of Medicine. His plinary approach to centenari-    

YASUMICHI ARAI received his Ph.D. in lipopro- tein metabolism of centenari- ans from the Keio University Graduate School in Tokyo,

NOBUYOSHI HIROSE is presently Assistant Profes- sor of the Department of Geri- atric Medicine, Keio Universi- ty School of Medicine, and a chief investigator of the Tokyo Centenarians Study. His

Keywords Reverse cholesterol transport · Lipoprotein lipase · Cholesteryl ester transfer protein · ABCA1 · Centenarian

French [20], Finnish [21], and Japanese centenarians [23, 24, 25]. It is of interest to investigate associations be- tween CETP deficiency and longevity in Japan, where the prevalence of the deficiency is extremely high and the life expectancy is longest around the world. It is also of worth to examine the hypothesis that rather a defect of risk factor for atherosclerosis, protective factors by na- ture 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 poten- tially antiatherogenic property. Numerous epidemiologi- cal 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 im- portant for preventing atherosclerosis [2, 3]. Reverse cholesterol transport (RCT), which enhances cholesterol efflux from the arterial wall and transport to the liver for reuse or excretion into bile, has been proposed as one of possible antiatherogenic mechanism of HDL. Cholester- yl ester transfer protein (CETP) is a carrier protein in RCT, which mediates the transfer of cholesteryl esters from HDL to apolipoprotein (apo) B-containing lipopro- teins, thus enhancing RCT. The role of CETP in athero- sclerosis remains controversial. Several mutations have been described at the CETP gene locus which cause de- pletion of CETP activity and consequently high HDL-C in plasma, especially in Japan [4, 5]. It has been demon- strated that CETP deficiency exhibits atherogeneity when combined with serum HDL-C level lower than 60 mg/dl [6] or with low activity of hepatic lipase [7]. In contrast, low CETP activity associated with the B2 allele of the Taq1B polymorphism may have protective roles against atherosclerosis [8]. Furthermore, CETP deficien- cy has been demonstrated to be associated with longevity in one study [4], and opposite result was obtained from another study [9, 10].

Methods

Subjects