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, V. Di Perna, F. Resta, M. Lovecchio, G. Chimienti, A.M. Colacicco, A. Capurso.

CNR-CSMME and the Department of Biochemistry and Molecular Biology, University of Bari, Via Orabona 4, 70126, Bari, Italy; the Center for Lipoprotein Metabolism and the Department of Geriatrics and Gerontology, University 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), which are 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. We compared the allele 347-360 frequencies, the lipoprotein concentrations and their association in centenarians and adults. In centenarians, 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 favorable 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), which in centenarians still exists as a trend. 

Centenarians show peculiar lipoprotein features: lower LDL-cholesterol (mean 103 vs. 115 mg/dl; P <0.02) and higher lipoprotein(a) (median 17.5 vs. 4.5; P <0.002). A 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, a 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

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 combination of allele variants can result in the protection against severe diseases or promotion of survival. Thus, successful aging would be characterized by a low frequency of risk alleles and the selective enrichment of favorable genotypes.

Human aging is generally described as a biological decline associated with damage to DNA, cells, tissues, and organs [1]. However, at present, aging is considered rather as a physiological remolding of biological functions. 

In this respect, few loci have been examined so far. Significant longevity-associations of HLA, apolipoprotein E, CIII, B, and angiotensin-converting enzyme coding regions [21,24,25]. The size polymorphism, due to the inter-individual variable number of the so-called kringle4 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 lifestyle [26,27], and is considered as an essentially genetic trait inversely related to the K4 repeat number [24,28]. Although the physiological and/or pathological roles of Lp(a) 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/dlText processed:

Lipoprotein concentrations were measured in centenarians and controls. The Friedewald formula [32] was used for calculating LDL-C. Nephelometry was used to measure serum apolipoprotein B and A-I levels. Lp(a) plasma concentrations were determined using the Immunozym Lp(a) Kit (Immuno-Vienna) by ELISA in duplicate. Samples were stored at -80C for a maximum of 1 month and thawed only once at the time of quantitation to avoid a significant effect of storage on the results [33]. 

The x2 test was used to compare allele frequencies in centenarians and controls estimated by gene counting. The linkage disequilibrium D for the pairs of loci was estimated by the methods of Nei [37]. Lipoprotein concentrations in the two groups were compared by the unpaired Students t test and U MannWhitney test (the latter employed for Lp(a), due to its non-Gaussian distribution). The association of the different apo A-IV polymorphisms with plasma lipoprotein levels was analyzed using the unpaired Students t test, the U MannWhitney test when comparing two groups, and one-way ANOVA and Kruskal-Wallis one-way ANOVA for comparison of three groups. The SPSS package was used for statistical analysis.