3.3. MTHFR

The 677C-T transition was analyzed in the elderly and young populations (Table 4). All comparisons failed to show differences in either genotype or allele frequency distributions between theOur study analyzed DNA from 282 individuals over 84 and 200 individuals aged younger than 17 years. This sample is not large enough to rule out weak genetic associations, like the putative effect of the 677C-T MTHFR mutation. However, our elderly sample was of a similar size to that of Schachter et al. (325 centenarians) [3] and larger than those of Davignon et al. (236 octogenarians) [5] and Kervinen et al. (95). The specific effect of this region of chromosome 19 on longevity was confirmed by examination of an apo C-I polymorphism, which is within 10 kb of apo E. Davignon et al. [5] found a significant decrease in the apo E4 allele frequency in Canadian female octogenarians, which was not found in the males. Although both our study and that of Davignon et al. [5] failed to detect an apo E:apo C-I association in males, this may have been revealed by a larger sample size. However, gender differences in apo E-related risks for late-onset diseases are not particularly surprising. Previous studies have reported a stronger association between apo E4 and Alzheimer's disease (AD) in females [19,20]. For example, in families with late-onset Alzheimer's disease, female apo E4 heterozygotes have higher risks for AD than those without apo E4, but the risks to heterozygote women are no greater than those for homozygotes. In men, the apo E4 homozygotes have higher risks than the heterozygotes and non-apo E4 carriers, but there was no significant difference in risks between apo E4 heterozygotes and non-apo E4 carriers [20]. In addition, recent work suggests that apo E has a significant effect on a larger set of lipid:apolipoprotein parameters in females compared to males [21]. Our study confirmed the importance of the ACE gene in longevity and the possibility of sex-specific effects by finding different ACE genotypes in the elderly women and men. Our old individuals were younger than the French centenarians (see Fig. 1). It is possible that the deleterious effects of the I allele manifest at an earlier age in males than in females. Schachter et al. explained the apparently paradoxical results they observed by suggesting that high blood pressure may be a protective factor in very old age [3]. However, the effects of this locus on longevity may involve non-cardiovascular manifestations, since neuroendocrine [23] and immunomodulator [24] activities have been proposed for this enzyme. A correlation between ACE activity in cortical tissue and increasing age may suggest an adaptive response to increasing needs during aging [25]. These studies highlight the importance of investigating genotype variation, in addition to allelic variation, in genetic studies of survival into old age. Genetic influences in the individual are determined by genotypes, and it is possible that certain combinations of deleterious and comparatively protective genotypes may result in an effect being masked if only allele frequencies are considered. This may occur if the impact of a heterozygous genotype is not midway between the two related homozygous states and if the frequency of a risk-related homozygous genotype is comparatively low. Such a scenario may be operating at the ACE locus. If the rare I:I genotype is deleterious and if the I:D and D:D genotypes are associated with similar risks, then it will be difficult to detect a change in the allele frequencies unless a larger sample is studied. Codon interchanges associated with apo E2, E3, and E4 are functionally associated with increasing risks for early death as suggested by earlier findings that the apo E4 allele is under-represented and apo E2 is over-represented in centenarians [3]. Apo E2 is not overrepresented in our elderly population. Perhaps this can be explained by the younger age of our sample. Alternatively, this finding and the relatively stronger influence of the apo C-I gene would be compatible with at least two other possibilities. First, other DNA variants in this region of chromosome 19 may also be of functional significance. Second, apo E2 may in certain cases be associated with a greater risk than apo E3. For instance, apo E2:3 individuals have greater risks of carotid artery atherosclerosis than apo E3:3 homozygotes [22]. There are a number of advantages of studying genotypes associated with longevity alongside disease-specific analyses. First, loci like apo E and maybe ACE may impact on different disease systems. Thus, the quantitative effect of allelic variation on longevity will be difficult to predict from disease-specific studies. Second, it is possible that a given allele can be beneficial and deleterious at various stages of life or that relatively deleterious and relatively(ACE) gene controls plasma ACE levels. Am J Hum Genet; [Year not provided]. Beohar N, Damaraju S, Prather A, et al. Angiotensin-converting enzyme genotype DD is a risk factor for CAD. J Invest Med; [Year not provided]: [Page numbers not provided]. Templeton AR. A cladistic analysis of phenotypic associations with haplotypes inferred from restriction endonuclease mapping or DNA sequencing. V. Analysis of case-control sampling designs: Alzheimer's disease and the apolipoprotein E locus. Genetics; [Year not provided]: [Page numbers not provided]. Chartier-Harlin MC, Parfitt M, Legrain S, et al. Apolipoprotein E (ε4) allele as a major risk factor for sporadic early and late-onset forms of Alzheimer's disease: analysis of the q chromosomal region. Hum Mol Genet; [Year not provided]: [Page numbers not provided].