Haplotype-based identification of a microsomal transfer protein marker associated with the human lifespan

Abstract

We previously reported a genomewide linkage study for human longevity using 308 long-lived individuals (LLI) (centenarians or near-centenarians) in 137 sibships and identified statistically significant linkage within chromosome 4 near microsatellite D4S1564. This interval spans 12 million bp and contains Ϸ50 putative genes. To identify the specific gene and gene variants impacting lifespan, we performed a haplotype-based fine-mapping study of the interval. The resulting genetic association study identified a haplotype marker within microsomal transfer protein as a modifier of human lifespan. This same variant was tested in a second cohort of LLI from France, and although the association was not replicated, there was evidence for statistical distortion in the form of HardyWeinberg disequilibrium. Microsomal transfer protein has been identified as the rate-limiting step in lipoprotein synthesis and may affect longevity by subtly modulating this pathway. This study provides proof of concept for the feasibility of using the genomes of LLI to identify genes impacting longevity.

Association of FOXO3A variation with human longevity confirmed in German centenarians

“…2 values were calculated from the allele counts. The obtained mean 2 of the G test statistics for the markers was 1.00, which reflected the good matching of the French sample collection (17). All German and French subjects gave informed, written consent before participation.…”

“…The analysis in the French centenarian sample generated a trend that supported the findings in the Japanese and German collections, but did not yield a statistically robust replication result. The validation could have been hindered by low levels of undetected population structure, but as demonstrated previously, the French sample shows no evidence of stratification (17). Another explanation might be the younger age of the French controls (18-70 years).…”

Lack of replication of genetic associations with human longevity

“…A sib-pair analysis strategy was adopted to identify a locus at D4S1564 (Puca et al 2001) that was subsequently investigated with haplotype based associations on 875 polymorphisms that identified a -493G/T MTP variant. This variant showed a consistent association in a second group of 250 centenarians and 250 controls selected to minimize the mahalanobis distance with respect to the cases to avoid stratification (Geesaman et al 2003) (Table 1). As for many other studies, the MTP association has not been reproduced in Caucasian European populations (Nebel et al 2005;Beekman et al 2006,) (Table 1).…”

Using high-throughput SNP technologies to study cancer

“…Candidate genes and regions are typically identified from linkage analysis, expression array analysis, knowledge of development and physiology; and comparative genomics. Tools such as the PANTHER database (Geesaman et al, 2003;Mi et al, 2005) and SNPEffect (Reumers et al, 2005) can be used to estimate the likelihood that a particular nonsynonymous coding SNP is causing a functional impact on the protein. The SNPSeek database (http://snp.wustl.edu/SNPseek/index.cgi) has now characterized over 90 000 coding SNPs in the exons of known genes.…”

“…First is that the case and control populations are not appropriately matched and the results observed might be reflective of an intrinsic difference between the populations examined, such as ethnic differences, and not due to the phenotype being studied. Several approaches have been proposed to restrict errors of this nature (Geesaman et al, 2003;Hinds et al, 2004). Alternatively, even with properly matched populations, chance alone will present differences between a case and control population unrelated to the phenotype under study.…”