related to longevity in a genome-wide scan. However, the association of MTTP with longevity has been contested in a large German collection of nonagenarians and centenarians. In this study, we made a detailed characterization of MTTP haplotype carrier status in a cohort of 1398 old men and women (mean age 78 years) compared to a population-based cohort (n777) of younger controls (mean age 40 years) in Oxford, England. Our results showed no significant differences in haplotypes for the MTTP gene between the younger and older age groups. Therefore, we provide reliable evidence against any significant association of the MTTP gene with longevity. Nebel and colleagues (8) were also unable to verify any association between MTTP haplotypes and longevity in a collection of 1589 nonagenarians and centenarians with appropriately matched controls using three single-nucleotide polymorphisms (SNPs) to form haplotypes in the MTTP gene.

It is important to note that many reported associations of genes with longevity in humans have not been replicated. The apolipoprotein E (APOE) gene is one of the few genes consistently associated with longevity, as the e4 variant predisposes to both Alzheimer's disease and cardiovascular disease. Since the candidate gene approach is unlikely to provide novel suggestions for longevity genes, it was of great interest that a region on chromosome 4 associated with longevity was implicated in a genome-wide scan.

The MTTP gene is highly heterogeneous, and determination of haplotype structure based on either two or three SNPs would provide a rather restricted view of the complex genetic variability in the MTTP gene. Therefore, we determined the haplotype frequencies based on 11 SNPs in an Oxford-based collection of 1451 old people and compared this with 777 population-based controls in the age range 30-50 years to assess possible associations of the MTTP gene with longevity. Although we recently observed an association between certain MTTP genetic variants and risk of cardiovascular disease, this association appeared to be unrelated to plasma low-density lipoprotein cholesterol concentrations. Interestingly, one of the polymorphisms examined in the haplotype-based identification of the MTTP gene for longevity, rs2866164, is in complete linkage disequilibrium (LD) with the MTTP-493G/T variant assessed in another study. It, therefore, seemed plausible that the increased risk of nonfatal and fatal cardiovascular disease associated with carriers of the MTTP-493T variant might explain the association of longevity with carriers of the MTTP-493G variant.

In conclusion, our study provides reliable evidence against any significant association of the MTTP gene with longevity. The haplotype distribution was based on 11 SNPs in the MTTP gene and yielded eight haplotypes with a frequency greater than 1%. There were no differences in the distribution of these haplotypes between the younger and older populations. No association of any of the 11 SNPs with age was detected within the population.The given text has several errors that need to be corrected. The corrected text is as follows:

A genome-wide scan in a long-lived North American cohort (4) identified a locus that had been challenged by a large German case-control study, which found no evidence for an association between MTTP gene haplotype, carrier status, and longevity. The original observation was also questioned by Bathum and colleagues in a study of 1651 92- to 93-year-old persons (13). They studied the effect of two of the original SNPs used by Geesaman and colleagues (5) but failed to find a difference in gene frequency compared with a smaller (n = 575) and younger (average age 53 years) control cohort. The present study reports no difference in haplotype frequencies for the MTTP gene between younger and older populations; this finding is consistent with the findings of the German case-control study. Nebel and colleagues pointed out that there may have been some evidence of bias in the North American younger control group, which is likely to have caused the positive identification of the MTTP gene in that study. We agree with the reasoning that the SNP allele frequency of the most crucial of the polymorphisms in the study of Geesaman and colleagues appears to be unbalanced. The MTTP-5038C/G (MTTP_rs2866164), MTTP-493G/T (MTTP_rs1800591), MTP-164C/T (MTTP_rs1800804), and MTTP I128T (MTP_rs3816873) are all in complete LD, are located on the same haplotype within the populations studied so far, and can therefore be compared with previously published studies. There is a surprisingly close range in distribution for the less common variant (0.25–0.29) within Caucasian populations: healthy 50-year-old Swedish men (0.25) (14), Irish diabetic persons (0.25) (15), Norwegian persons with familial hypercholesterolemia (0.26) (16), moderately hypercholesterolemic Scottish men (0.26) and Scottish men with cardiovascular disease (0.26) (7), and Framingham men (0.29) and women (0.26) (17). This is in contrast to the results in the control population reported by Geesaman and colleagues which show a frequency of 0.34 (5).