HI represents the rs2866164-G(cid:2)MTP-H95 haplotype, and HII collectively represents the other two haplotypes.

in a U.S.-based longevity study. Although there was evidence of statistical distortion at this locus in a French-based longevity study, there was no significant difference in allele frequencies with respect to the risk haplotype identified from the former study. Although apparently a discrepancy (a significant and replicated finding not validated in a third sample), the most likely explanation is a lack of power of individual studies. If one examines the odds ratios estimated for the two unstratified U.S. studies [combined OR 0.72 (0.58, 0.89)] and the French study [OR 0.94 (0.78, 1.14)] we see their confidence bounds overlap significantly (suggesting no discrepancy necessarily exists). Tak- ing a plausible intermediate genetic model to explain this association to exceptional longevity consistently (e.g., fre- y   quency 0.70, genotype relative risk 0.83), we find that even a sample as large as the French replication sample of 500 cases and 500 controls would have only 50% power to reach nominal are| statistical significance (P 0.05) given the modest individual effect of this allele. Thus, even if we assume the effect is true and present equally in all study samples, half of all studies of this ws MY.> ( magnitude will record a nominally ‘‘negative’’ result (P 0.05). This calculation underscores the general observation that asso- ciation studies of complex phenotypes are likely to require extremely large samples to convincingly elucidate the modest genetic influences involved.

Other groups have found genetic associations between MTP and several phenotypes including lipoprotein profiles, insulin resistance, and fat distribution, and most of these studies focused  Mie3/1 on the 493G T marker (38–44). Like so many other mapping studies of complex traits, the literature surrounding MTP has been complex and often contradictory, although as a general 4 trend the 493T allele has been associated with detrimental phenotypes.

The known activity of MTP, as a rate-limiting step in lipid metabolism, lends functional credibility to our association of MTP with human longevity. Coronary artery disease and other vasculopathies attributed to unfavorable lipid profiles (periph- eral vascular disease, renal-vascular disease, and stroke) account for a large percentage of human mortality. Common genetic variants that impact the function of lipid metabolism should be expected to impact human lifespan; for example, the offspring of centenarians have higher levels of high-density lipoprotein (good cholesterol) and lower levels of low-density lipoprotein (bad cholesterol) than age-matched controls, and they demonstrate significantly lower risks of heart disease and stroke compared with age-matched controls (45, 46). In addition, a ‘‘longevity syndrome’’ was described among families with extremely low levels of low-density lipoprotein particles (47). Although rea- sonable to believe that the impact of MTP on human longevity is through its impact on lipid profiles, the association studies above suggest that this gene may also affect susceptibility to insulin resistance and obesity.

Although not necessary to explain the data, it is worth noting that other factors could very likely contribute to inconsistency among the studies. Among the possibilities relevant to this particular study are two worth noting:

risk allele in the different populations. Diet is one obvious possibility; the culinary tastes of Europeans and Americans may place different stresses on equivalent genetic backgrounds. The interaction between the ApoE gene, diet, genetic background, and other covariates has now been well documented (27, 28), and it is reasonable to assume that much of the variance in human longevity will be explained by complex interactions between environment and genetics.

MTPand ApoE.There are many parallels between the associations of MTP and ApoE. Both genes are risk factors implicated in cardiovascular disease and longevity, the latter being also being associated with Alzheimer’s disease (AD). In light of this, it would be intriguing to explore the genetic epidemiology of MTP with respect to diseases of aging, such as AD. Using the well-matched set of 250 LLI and controls, we confirmed in our   LLI and control samples that the ApoE 2 allele is protective vam63 wav» 64 (12% vs. 7%), the 3 allele is neutral (83% vs. 80%), and the 4 allele is detrimental (5% vs. 13%) with respect to lifespan   extension (P 0.0001, Table 10, which is published as supporting information on the PNAS web site). No interaction between the MTP and ApoE alleles with respect to lifespan was detected, although the sample size may have been inadequate.

(ii) The American and French samples have important phe- notypic differences. For example, the average age of the Amer- ican controls was much younger than the French controls. Second, the French study involved a smaller fraction of male centenarians compared with the American study. Because the ascertainment strategies were different for the two studies, this may at least partially explain this discrepancy.

Implications. Our study lends credence to the claim that cente- narians and near-centenarians offer an appealing model for studying human longevity and disease resistance (45). We have confirmed the hypothesis that a population that has escaped or delayed the lethal pathologies of old age is likely to be helpful in studies to detect genetic factors that impact the diseases of aging (48). By systematically examining a large stretch of the genome for genes associated with a phenotype, we have provided cred- ibility to the use of public gene maps and SNP databases to perform studies of the full genome. As our study mapped 0.5% of the genome, it would have required a 200 times larger study to scan the entire genome. Because MTP can explain only a small