Elsevier

Atherosclerosis

Volume 137, Issue 2, April 1998, Pages 407-417
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 centenarians

https://doi.org/10.1016/S0021-9150(97)00290-6Get rights and content

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, HinfI347 (alleles +, −) and Fnu4HI360 (alleles 1, 2), and a VNTR (alleles 3, 4) at the 3′ region of the apo A-IV gene. The allele frequencies, the lipoprotein concentrations and their association in centenarians and adults have been compared. In centenarians, the HinfI genotype distribution is different (P<0.05) and the (+13) haplotype is prevalent (0.54 vs. 0.39), with a greater association of (+3), indicating the selection of a favourable allele. The lipoprotein modulation by the apo A-IV polymorphisms is suggested by significant associations in adults ((+/+) 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 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). Large part of them (47%), especially the Hinf(+/+) and the (+13) homozygotes, have a lipoprotein(a) >20 mg/dl, value considered as the threshold for atherogenic risk, surprisingly compatible with healthy longevity.

Introduction

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

In this respect, few loci have been examined so far. Significant longevity-associations of HLA, apolipoprotein E, CIII, B and angiotensin-converting enzyme alleles have been found 2, 3, 4, 5. Other genes could influence human survival, thus it is necessary to check as many loci as possible, not only in populations of different genetic backgrounds, but also in closer groups, probably living in different environments. In particular, genetic factors affecting lipid metabolism can be important for susceptibility or resistance to atherogenic mechanisms. 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.

First, we focused our attention on apo A-IV. The gene, localized at the 11q23-qter locus has a well known sequence and genomic organization 9, 10. The protein has also been sequenced and its structure has been predicted 11, 12. A possible role of apo A-IV has been suggested in the assembly and metabolism of the HDL, in reverse cholesterol transport and activation of lecithin-cholesterol acyltransferase (LCAT) and lipoprotein lipase (LPL)[13]. Several common and rare isoforms have been detected in a broad range of populations with different ethnic backgrounds and the corresponding allelic variations have been analyzed 12, 14, 15, 16. The effect of the different isoproteins on plasma lipid and apolipoprotein concentrations is still controversial 6, 14, 17, 18, 19, 20. We studied the two common restriction site polymorphisms at codons 347 (Hinf347) and 360 (Fnu360), and the (CTGT) VNTR in the 3′ untranslated region [16], examining their respective frequencies in centenarians and adults, in search of a longevity-associated allele. We also investigated whether the lipid, apolipoprotein and lipoprotein plasma concentrations were peculiar in centenarians and explored the existence of some association with the apo A-IV polymorphism that could be related to the longevity unaffected by atherogenic disorders. Secondly, we focused on Lp(a), the LDL-like particle characterized by the unique apo(a) protein 21, 22. The human apo(a) gene has been localized at the 6q2.6–2.7 locus and the cDNA cloned and sequenced [23]. The apo(a) gene has a two order heterogeneity: a size polymorphism and sequence alterations in coding and non-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 related 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 normal adults, and verify the possible association of this feature with the apo A-IV polymorphism.

Section snippets

Subjects

A total of 71 centenarians (18 men and 53 women, 100–107 years of age, mean=102.3 years) were recruited using the Central Population Register of Apulia. They were self-sufficient and lived at home. Admission criteria excluded acute-phase reactions or chronic disorders such as diabetes, malignancy, nephropathy or end-stage renal disease, cardiac failure, myocardial infarction and dementia. They were not on medications known to affect lipids. All these subjects were analyzed for the standard

Results

The apo A-IV polymorphism was analyzed by genotyping (Fig. 1a,a′,a′′). The Thr347→Ser change, that eliminates a HinfI site, was identified by the presence (allele+) or absence (allele−) of the restriction site in the 244 bp amplified fragment. The Gln360H→His change, that results in the loss of a Fnu4HI site, was separately identified by the presence (allele 1) or absence (allele 2) of this cutting site in the same amplification product. The VNTR alleles were identified by direct gel

Discussion

We have studied the apo A-IV polymorphism in Apulian centenarians searching for longevity/associated allele frequencies by comparing them with adults of the same region.

The Hinf347 locus shows a significant difference in the genotype distribution with the prevalence of the (+/+) homozygosity in centenarians. No significant differences are observed at the Fnu360 locus. The VNTR, that proved to be diallelic in every cases, appears not to be so informative as other repeat markers. However, it is

Acknowledgements

We thank Mr Vito Cataldo for the reproductions. This work was supported by the CNR-Targeted Aging Project grants No. 95.982.PF40, 95.973.PF40, 95.988.PF40 code no. 981740 and by MURST grants. The financial support of Telethon-Italy (G. Pepe-grant No. 951) is also gratefully acknowledged.

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