Fig. 3. Lp(a) isoforms in centenarians divided into groups with respect to the Lp(a) plasma concentrations expressed as mg:dl.

observation of others that the ((cid:28)) allele lowered the level of these two parameters [16]. Conversely, the (1:1) homozygotes have higher TG and apo B values than the (1:2) heterozygotes, in agreement with other data [18,19]. Our findings confirm the existence of a relation- ship between the apo A-IV polymorphisms and plasma lipoproteins in adults and support the modulating func- tion of the apo A-IV alleles. Again, the different sex ratio and age range of the populations studied so far, as well as the responsiveness to different diets, could ex- plain some discrepancies with other reports. In cente- narians, these associations, that presumably confer advantage, still exist and can be trended clearly, though the values do not show the statistical significance prob- ably because of a certain attenuation of the allele modulating effect with aging (some hiding effect of the relatively small sample size cannot be of course ex- cluded). In centenarians, the relevant data is the signifi- cant association of the Hinf polymorphism with the Lp(a) concentration, the ((cid:27):(cid:27)) homozygotes having a higher value than the ((cid:27):(cid:28)) heterozygotes. This is consistent with the high incidence of the ((cid:27):(cid:27)) geno- type, and the large number of centenarians (47%) hav- ing an Lp(a) concentration higher than 20 mg:dl. As far as the VNTR is concerned, it does not appear to be significantly related to the lipoprotein parameters. However, some gradient concentrations (i.e. of LDL-C and TG) can be observed, and in particular the associa- tion of the (3:3) and ((cid:27)13) genotypes with the in-

creased Lp(a) medians (although with no significant P value) can be clearly seen in centenarian group, were these genotypes are the most frequent. With reference to the proposed role of apo A-IV [13], the modulation of LPL activity, which hydrolyzes VLDL, may affect the level of LDL-C. The modulation of reverse choles- terol transport and LCAT activity may affect the level of HDL-C. Thus, according to the protein sequence and its deduced structure [11,12], changes of either amino acid 347 or 360 can, in turn, modify the domain where they are located. The allele variants of these loci could act on the above mentioned mechanisms and influence the physiological functions of the molecule, presumably with a different impact on each lipoprotein class. An example is the inverse relationship of both LDL-C and apo B with the two loci, which we found in adults and centenarians, probably resulting in the bal- anced lipoprotein levels. VNTR, which is located in the non-coding apo A-IV region, has probably no a direct effect, when considered on itself. The relation with the higher Lp(a) concentrations observed in centenarians is possibly the consequence of the great association with the ((cid:27)) variant at the Hinf locus which is significantly associated to this parameter. It is difficult at present to explain a functional interaction between two apparently unrelated genes such as apo A-IV and apo(a). However, each of these genes, in its own way, could be involved in the pathophysiology of the cardiovascular system. From our data the hypothesis can be put forward of a

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