To the Editor: Dr Barzilai and colleagues1 reported that families with exceptional longevity have significantly larger high-density lipoprotein (HDL) and low-density lipoprotein (LDL) particle sizes, which are associated with increased homozygosity for the codon 405 isoleucine to valine (I405V) variant in the cholesteryl ester transfer protein (CETP) gene. These results, however, are at odds with previous studies. For instance, this genotype has been associated with increased risk of coronary artery disease (CAD) in the Copenhagen City Heart study.2 Studies have also found that genetically determined deficiency of CETP activity may contribute to increased levels of possibly dysfunctional HDL cholesterol, which may actually increase risk of ischemic heart disease.2 Based on 1749 consecutive patients with acute myocardial infarction, we have reported that this genotype is correlated with the extent of CAD on angiography.3 Finally, homozygosity for this allele was not found to be independently associated with CAD in a study that evaluated 112 candidate gene variants in 5061 individuals of Japanese origin.4
The genetic and environmental factors underlying longevity are undoubtedly complex and a genetic predisposition for longevity is not necessarily protective CAD. Nonetheless, we think it is unlikely that this genotype could consistently improve longevity given the contradictory reports of its association with CAD, which is the leading cause of mortality in the industrialized world.
Data from association studies, such as that of Barzilai et al,1 should be evaluated in the context of their methodological limitations. The chance of a false linkage in association studies is high, the linked gene variants have not always been associated with a biologically relevant pathophysiological mechanism, and the replication of the findings, even in the same population, has been limited.5 Until the hypothesized association between a "healthy aging phenotype and genotype" is supported by large-scale epidemiological data and a clear pathophysiological mechanism, the chance of a false linkage association cannot be excluded.
Financial Disclosures: Dr Andrikopoulos receives a research fellowship from the Hellenic Heart Foundation. Drs Andrikopoulos and Richter both receive research fellowships from the European Society of Cardiology.
Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature
Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal
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