ATHEROSCLEROSIS

In search of a biological pattern for human longevity: Impact of apo A-IV genetic polymorphisms on lipoproteins and the hyper-Lp(a) in

G. Pepe a,*, V. Di Perna a, F. Resta b, M. Lovecchio b, G. Chimienti a, A.M. Colacicco b, A. Capurso b

a CNR-CSMME and Department of Biochemistry and Molecular Biology, Uni6ersity of Bari, Via Orabona 4, 70126, Bari, Italy b Center for Lipoprotein Metabolism and Dept. of Geriatrics and Gerontology, Uni6ersity of Bari, Via G. Cesare, 70124Bari, Italy

Received 5 May 1997; received in revised form 5 November 1997; accepted 20 November 1997

Abstract

We studied centenarians to investigate the biological basis of human longevity focusing on the apolipoprotein A-IV and lipoprotein(a), potentially involved in the susceptibility to atherogenic mechanisms. We analyzed two restriction polymorphisms, % HinfI (alleles (cid:27), (cid:28)) and Fnu4HI (alleles 1, 2), and a VNTR (alleles 3, 4) at the 3 region of the apo A-IV gene. The allele 347 360 frequencies, the lipoprotein concentrations and their association in centenarians and adults have been compared. In centenarians, B the HinfI genotype distribution is different (P 0.05) and the ((cid:27)13) haplotype is prevalent (0.54 vs. 0.39), with a greater association of ((cid:27)3), indicating the selection of a favourable allele. The lipoprotein modulation by the apo A-IV polymorphisms is suggested by significant associations in adults (((cid:27):(cid:27)) homozygotes have lower LDL-cholesterol and apo B than heterozygotes; (1:1) homozygotes have higher TG and apo B than heterozygotes), that in centenarians still exists as a trend. Centenarians show B peculiar lipoprotein features: lower LDL-cholesterol (mean 103 vs. 115 mg:dl; P 0.02), and higher lipoprotein(a) (median 17.5 B \ vs. 4.5; P 0.002). Large part of them (47%), especially the Hinf((cid:27):(cid:27)) and the ((cid:27)13) homozygotes, have a lipoprotein(a) 20 mg:dl, value considered as the threshold for atherogenic risk, surprisingly compatible with healthy longevity. © 1998 Elsevier Science Ireland Ltd. All rights reserved.

Keywords: Aging; Apo A-IV; Apo(a); Allele-variants; Haplotype; Lipoproteins

1. Introduction

logical functions. Longevity is probably the result of a lucky interaction of non genetic and genetic factors. Some genes can cause or predispose to age-related disorders. Different alleles of these genes or different genes, in association or ‘per se’, are possibly involved in longevity, each having a small effect: the right combina- tion of allele variants can results in the protection against severe diseases or promotion of survival. Thus, a successful aging would be characterized by a low frequency of ‘risk’ alleles and the selective enrichment of ‘favourable’ genotypes.

Human aging is generally described as a biological decline associated with damaging of DNA, cells, tis- sues, and organs [1]. However, at present, aging is considered rather as a physiological remoulding of bio-

Abbre6iations: Apolipoprotein(a), apo(a); Apolipoprotein A-IV, apo A-IV; Apolipoprotein B, apo B; Apolipoprotein B:LDL-choles- terol ratio, B:L; Cardiovascular disease, CVD; Coronary artery dis- ease, CAD; Enhanced chemiluminescence, ECL; Lipoprotein (a), Lp(a); Total cholesterol, TC; Triglycerides, TG; Variable number of tandem repeat, VNTR.

In this respect, few loci have been examined so far. Significant longevity-associations of HLA, apolipo- protein E, CIII, B and angiotensin-converting enzyme

* Corresponding author. Tel.: (cid:27)39 80 5443312; fax: (cid:27)39 80 5443317.

coding regions [21,24,25]. The size polymorphism, due to the inter-individual variable number of the so-called ‘kringle’4 domain (K4), is considered the major factor responsible for the high variation in the plasma Lp(a) \ concentration, ranging from 0.1 to 100 mg:dl. This feature is thought to be scantily influenced by age, sex, menopausal status, diet or life-style [26,27], and is considered as an essentially genetic trait inversely re- lated to the K4 repeat number [24,28]. Although the Lp(a) physiological and:or pathological roles are still unresolved, high plasma concentrations are associated, at least in Caucasians, with an increased risk of CAD and CVD, both independently and in correlation with other genetic determinants including the apo A-IV polymorphism [29]. A value of 20 mg:dl has been proposed as the risk threshold [8]. On the basis of the above considerations, we decided to compare the plasma Lp(a) levels of centenarians with those of nor- mal adults, and verify the possible association of this feature with the apo A-IV polymorphism.

alleles have been found [2–5]. Other genes could influ- ence human survival, thus it is necessary to check as many loci as possible, not only in populations of differ- ent genetic backgrounds, but also in closer groups, probably living in different environments. In particular, genetic factors affecting lipid metabolism can be impor- tant for susceptibility or resistance to atherogenic mech- anisms. It has been proposed that the gene for the apolipoprotein A-IV (apo AI-V) can play a role through the modulation of plasma lipid parameters by its isoproteins [6]. Recently, the apoprotein(a) (apo(a)) has been suggested to be a genetic determinant of lipoprotein(a) (Lp(a)) plasma concentration due to its size polymorphism and thus, contribute to coronary artery and cerebro-vascular disorders (CAD and CVD) [7,8]. Consequently, both the apo A-IV and the apo(a) gene can potentially have a role as ‘longevity genes’. Their impact on human survival deserves further investigation.

The centenarians who achieve very long life-spans in the absence of severe disorders offer an useful model to investigate the biological basis of human longevity. We have studied the centenarians from Apulia, in Southern Italy, in comparison to normal adults from the same region.

2. Methods

2.1. Subjects