4q25, Microsomal Transfer Protein and Human Longevity: Novel Data and a Meta-Analysis of Association Studies

Marian Beekman, Gerard Jan Blauw, Jeanine J. Houwing-Duistermaat, Bernd W. Brandt, Rudi G. J. Westendorp, and P. Eline Slagboom

1 Molecular Epidemiology, 2 Gerontology and Geriatrics, Department of General Internal Medicine, and 3 Medical Statistics, Leiden University Medical Center, The Netherlands.

Recently, chromosome 4q25 was linked to exceptional human longevity, and a haplotype of the positional candidate microsomal transfer protein (MTP) gene was associated with the phenotype in U.S. Caucasians. We investigated whether linkage to 4q25 could be detected in 164 nonagenarian sibships of the Leiden Longevity Study. Additionally, we compared the MTP 493G/T and Q95H allele and haplotype frequencies in the Leiden Longevity Study (379 nonagenarians, 525 of their offspring, and 251 partners of their offspring) and in the Leiden 85-Plus Study (655 octogenarians and 244 young controls). The latter study population was followed for at least 7 years, providing the opportunity to perform prospective analyses using longitudinal data. We found no evidence for linkage at 4q25 or association of the MTP locus with longevity in nonagenarian individuals. Meta-analyses of all previous studies implied that the association in U.S. Caucasians may have its source in admixture of the U.S. control population rather than in the genetic effect of the locus on exceptional longevity.

Long-lived sibling pairs represent the extreme tail of the distribution of human lifespan; they have a history of aging slowly and either markedly delay or escape age-associated diseases. Influencing human lifespan and reaching old age in good health remains a wish for many people. Human variation in lifespan is influenced by three main factors: (i) unique environmental factors (e.g., an individual's diet or hazardous line of work); (ii) familial environmental factors (e.g., familial socioeconomic status); and (iii) genetic factors (e.g., genetic susceptibility to cancer). Environmental factors are hard to study in humans. Current genetic research on longevity aims to identify the genes involved in the ability to become long-lived from the perspective that such genes may indicate the major relevant pathways of human lifespan regulation. Evidence for the inheritance of longevity was provided by the finding that siblings of centenarians have a much higher chance of reaching the age of 100 years than do siblings of controls from the same birth cohort. Furthermore, the study of the comprehensive population-based genealogy database of the Icelandic population shows that a clear familial component is present in longevity. This hereditary component could represent shared environmental factors as well as shared genetic factors. From twin studies, it was estimated that approximately 25% of the variation in lifespan is attributable to genetic variation. However, the genetic basis of the inherited component of longevity still remains to be elucidated.

Because the 4q25 locus was also suggestively linked to healthy aging in a small study of 70-year-old U.S. male veterans, it can be questioned whether this locus is of importance only for attaining the most exceptional longevity. The search for genes having a major influence on longevity could be started by performing a genome scan. We therefore performed linkage analysis in the chromosome 4q25 linkage region in 379 nonagenarian participants belonging to 164 sibships from the Leiden Longevity Study. Recently, we have reported excessive survival in three generations of relatives of these nonagenarian sibling pairs, demonstrating that our selection criteria result in individuals carrying familial longevity effects. Additionally, we performed association analysis of the two-SNP haplotype of the MTP gene in the nonagenarian sib pairs, the offspring of these sib pairs (assuming that they are predisposed to be long-lived), and the partners of the offspring (assuming that they represent the general population). Furthermore, we investigated the first and second cohorts of the prospective population-based Leiden 85-Plus Study for association with the two-SNP haplotype of the MTP gene. Association of the two MTP SNPs was tested cross-sectionally by comparing allele frequencies in the octogenarians with those in a young control group from the same Leiden area, as well as prospectively by testing (using the follow-up data) the effects of the MTP genotypes on survival after the age of 85. Finally, we performed a meta-analysis of all known data on the MTP T-Q haplotype and longevity to estimate the odds ratio of this putative risk haplotype on survival in Caucasian populations.

Participants: Leiden Longevity Study

The individuals investigated in the present study participate in the ongoing Leiden Longevity Study. Families participating in the Leused to represent the previously associated haplotype. The haplotype frequencies did not differ significantly between the case and control groups in the Leiden Longevity Study or in the Leiden 85-Plus Study. Sex-specific analyses also did not reveal any association of these polymorphisms. 

In summary, this study examined the association of MTP gene polymorphisms with longevity in two Dutch populations. The study found no significant association between the MTP gene polymorphisms and longevity in either population. The study used rigorous genotyping methods and adhered to ethical guidelines for research involving human subjects. The results suggest that other genetic or environmental factors may play a stronger role in determining longevity in these populations.population for their analysis, which might have reduced the impact of population stratification. However, the absence of association in our study and in other European studies suggests that the MTP gene may not play a significant role in human longevity in European populations.