ANALYSIS OF THE APO-E APO-C-I, ANGIOTENSIN-CONVERTING ENZYME AND METHYLENETETRAHYDROFOLATE REDUCTASE GENES AS CANDIDATES AFFECTING HUMAN LONGEVITY

Genetic factors are likely to affect human survival, since twin studie s have shown greater concordance for age of death in monozygotic compa red to dizygotic twins. Coronary artery disease is an important contri butor to premature mortality in the UK. Accordingly, we have chosen ge nes associated with cardiovascular risk, apo E/apo C-I, angiotensin co nverting enzyme (ACE) and methylenetetrahydrofolate reductase (MTHFR), as candidates which may affect longevity/survival into old age. An as sociation study was performed by comparing allele and genotype frequen cies at polymorphic loci associated with these genes in 182 women and 100 men aged 84 years and older with 100 boys and 100 girls younger th an 17 years. MTHFR allele and genotype frequencies were similar in the elderly and young populations. Apo C-I allele and genotype frequencie s were significantly different in the elderly women compared to the yo unger sample (P < 0.05). No difference was observed in the elderly men . At the neighbouring apo E gene, we only observed a difference betwee n genotypes in the elderly women and the young sample; however, this d id not retain significance when the genotype frequencies of the young sample were adjusted to values expected from the allele frequencies on the basis of Hardy-Weinberg equilibrium and compared to observed geno types in elderly men and women. In contrast to previous studies, apo E 2 was not overrepresented in the elderly men or women. Thus, the propo sition that apo E2, E3 and E4 protein isoforms are themselves function ally associated with increasing risks for early death, may be too simp listic. The I/I ACE was depleted in the elderly males but not the elde rly females. Furthermore, significant differences were observed betwee n ACE genotypes in elderly men and elderly women. These data suggest t hat the penetrance of loci which influence survival may vary according to sex. The depletion of the ACE I/I genotype in elderly men is gener ally consistent with a previous study which found decreased frequencie s of the I allele in French centenarians compared to younger controls. However, these results are apparently paradoxical, since others have suggested that the I allele is associated with increased cardiovascula r risk. Clarification of the overall effect of a genotype on survival will be vital if therapies are to be considered which target specific genetic variants. (C) 1997 Elsevier Science Ireland Ltd.