Genetic associations with humanlongevity at the APOE and ACEloci

Francois Schachter, Laurence Faure-Delanef, Frédérique Guénot, Hervé Rouger,Philippe Froguel, Laurence Lesueur-Ginot & Daniel Cohen

in an emfort to dissect tne genetic Components OF longevity, we Nave unaerlaken Case-control studies of populations of centenarians (n=338) and adults aged 20~70 years atseveral polymorphic candidate gene loci. Here we report results on two genes, chosen fortheir impact on cardiovascular risk, encoding apolipoprotein E (ApoE), angiotensin-converting enzyme (ACE). We find that the e4 allele of APOE, which promotes prematureatherosclerosis, is significantly less frequent in centenarians than in controls (p<0.001), whilethe frequency of the €2 allele, associated previously with type Ill and IV hyperlipidemia, issignificantly increased (p<0.01). A variant of ACE which predisposes to coronary heartdisease is surprisingly more frequent in centenarians, with a significant increase of thehomozygous genotype (p<0.01). These associations provide examples of genetic influenceson differential survival and may point to pleiotropic age-dependent effects on longevity.

and apoE4 . These alleles have a major impact on total andLDL-cholesterol levels in the serum, which in turn arehighly correlated with risk for atheroscleroticcardiovascular disease. The €4 allele has been associatedwith ischaemic heart disease in several studies’. Aninsertion (I)/deletion (D) polymorphism in the ACE geneisassociated with a major gene effect on theinter-individualvariability of plasma ACE concentration” and the deletionpolymorphism has been identified as a risk factor formyocardial infarction".In arder to cearch far cenetic influences on human

Although there is ample evidence supporting thecontention that a genetic component contributes to thedetermination of human longevity'“ the only associationreported so far was found at the HLA locus in twoindependent investigations**. These studies included lessthan 100 centenarians. Since cardiovascular diseases areamong the leading causes of death’ and their underlyinggenetic causes have been extensively studied, we decidedto investigate possible associations between longevity andalleles of three already characterized candidate genes,coding for apolipoprotein E, apolipoprotein B andangiotensin- -convertin enzyme (ACE)a tg    

In order to search for genetic influences on humanlongevity, a population of 300 French centenarians(individuals in their 100th year and beyond) was collected,to be compared with a control group of 160 French adults,aged 20-70. These populations were typed by DNAamplification for alleles of APOE" and ACE’. 

 NE ESAPOEhas three common alleles’, designated €2, €3 and4, which code respectively for the isoforms apoE2, apoE3

APOE allelesWL. 4 21121. £2...

The €4 allele frequency was significantly decreased (5.2%versus 11.2%, p<0.001) while the €2 allele frequency wassignificantly increased (12.8% versus 6.8%, p<0.01) inthe centenarian group (Table 1). The p’” values were lessthan 10° for e4 and less than 10~ for €2 when data for asecond control group already genotyped were pooledwith the new control population (Table 1). The oddsratios, a measure of the relative chance of becoming acentenarian between subjects with or without a givenallele, were 2 and 0.43 for the €2 and the €4 alleles,respectively.

Populations are in Hardy-Weinberg equilibrium for APOE alleles.Significantly higher than controls (p<0.01 and p<0.001 when both controlpopulations are pooled).®Significantly lower than controls (p<0.001 and p<10* when both contro!populations are pooled).

ACE alleles and genotypesTTL. AOI LW. Dp cthe cet cen ccc,

nn” ON EEThe ACE allele distribution was shifted in centenarians,with an increase of the DD genotype (39.6% versus 25.6%,29

 Table 2 Distributions of ACE genotypes andalleles In controls and centenarians ACE genotypes Centenarians Controls Other control(n=310) (n=164) populations (n=553)number (frequency) number (frequency) Lille, Strasbourg,Toulouse" number(frequency)DD 434 (0.396) 42 (0.256) 157 (0.284)ID 148 (0.438) 91 (0.555) 295 (0.533)" 56 (0.166) 31 (0.189) 101 (0.183)ACE alleles Centenarians Controls Other controlnumber (frequency) number (frequency) populationsNancy, Lille,Strasbourg, Toulouse"*"*number (frequency)D 416 (0.615) 175 (0.533) 345 (0.555)1 260 (0.385) 153 (0.467) 276 (0.445)  ee  Table 4 Sex-related differences in centene APOE alleles €2 £3 €Females (n=282) 0.128 0.823 0Males (n=41) 0.122 0.805 0ACE genotypes DD DtFemales (n=294) 0.395 0.442 0Males (n=44) 0.409 0.409 0The numbers shown are allele and genotype freqThere is no significant difference male and femalecentenarians for any of these frequencies, at the §confidence level or between controls and centenzone sex.However, 41 male centenarians were typed for /44 for ACE, which allowed a comparison betwThere wac non cionificant cev_related difference

Table 4 Sex-related differences in centenarians

The numbers shown are allele and genotype frequencies.There is no significant difference male and femalecentenarians for any of these frequencies, at the 5%confidence level or between controls and centenarians ofone sex.

However, 41 male centenarians were typed for APOE and44 for ACE, which allowed a comparison between sexes:There was no significant sex-related difference in any ofthe allele frequencies, whether for APOE or ACE (Table4). Searching for interactions between loci revealed atrend of negative correlation, that did not reach statisticalsignificance, between thee2 alleleof APOEand the deletionallele of ACE (Table 5).