No association between microsomal triglyceride transfer protein (MTP) haplotype and longevity in humans

Almut Nebel*, Peter J. P. Croucher†, Rieke Stiegeler‡, Susanna Nikolaus‡, Michael Krawczak†, and Stefan Schreiber*‡§

Institutes for *Clinical Molecular Biology and †Medical Informatics and Statistics and ‡Hospital for General Internal Medicine, University Hospital Schleswig–Holstein, 24105 Kiel, Germany

Edited by Louis M. Kunkel, Harvard Medical School, Boston, MA, and approved April 20, 2005 (received for review November 22, 2004)

position 95 (8). Additional support for an influence of MTP gene variation upon longevity was obtained by the replication of the initial haplotype association in independent sets of 250 proac- tively matched U.S. Caucasian cases and controls (5). However, in the same study, no haplotype frequency differences were detected in a large French sample. Only a departure from the Hardy–Weinberg equilibrium was observed among French long- lived individuals (LLI) but not in the controls (5).

Human longevity is a multifactorial condition with a significant genetic contribution. A recent association study in two indepen- dent samples of long-lived U.S. Caucasians [long-lived individuals (LLI)] identified a SNP haplotype of the microsomal triglyceride transfer protein (MTP, 4q25) that was underrepresented among LLI when compared with younger controls. This suggested that vari- ation in the MTP gene might modify human longevity. Because of its function in lipid metabolism, the MTP gene product could plausibly play a pivotal role in the physiology of aging. However, the association observed in the U.S. samples could not be repli- cated by the same authors in a larger French LLI sample. We have therefore investigated the MTP ‘‘risk’’ haplotype in our own collection of 1,589 German nonagenarians, centenarians, and ap- propriately matched controls. No statistically significant differ- ences were observed between LLI and controls at the allele, genotype, or haplotype level. This indicates that a noteworthy influence of the respective MTP haplotype on human longevity in the German population is unlikely. Furthermore, in comparison with all other U.S. and European samples analyzed, the MTP ‘‘risk’’ haplotype was found to be overrepresented only in the U.S. controls. This implies that the putative association is more likely to reflect recent changes in the genetic structure of the U.S. Caucasian population as a whole, rather than genetic effects upon survival to old age. In our view, the original study therefore highlights potential problems that arise when the case-control design is used as a means to map longevity genes in humans.

The MTP gene product has been proposed to be involved in the correct assembly of very low-density lipoprotein and chylo- micron particles (9), and drugs that inhibit MTP activity improve lipoprotein profiles (10). This function appears to lend addi- tional credibility to an association of MTP gene variation with human longevity, because coronary artery disease attributed to unfavorable lipid profiles is one of the major causes of death in the western world (5). However, in view of the observed dis- crepancies between the U.S. and French samples and the con- sequent uncertainty about the possible involvement of MTP in human longevity, we attempted to replicate the findings of Geesaman et al. (5) in an extensive collection of unmf>1 1,000 LLI and 550 controls of German ancestry. In our view, the observed lack of notable haplotype frequency differences in the German samples highlights the particular problems arising from the inherent absence of age-matching in case-control longevity studies.

Subjects and Methods

Study Population. The ‘‘case’’ sample comprised 1,039 unrelated individuals of German ancestry who were between 95 and 109 years of age at the time of recruitment (mean age, 98.2 years). They represented the top percentiles of the respective birth cohort-specific age distributions (95th percentile for females and 98th percentile for males). Three hundred seventy-three (36%) of the long-lived participants were centenarians or supercente- narians (mean age, 101.4 years). The sex ratio in the entire sample was 74% females vs. 26% males.

ongevity in humans can be thought of as a multifactorial condition to which both genetic and environmental factors are likely to contribute. Studies in twins have shown that longevity is moderately heritable, and that genetic variation accounts for   25% of the observed variation in life expectancy (1, 2). Similarly, family studies of centenarians from the U.S. and Iceland have indicated a significant genetic component of lon- gevity (3, 4).

Nonagenarians and centenarians were recruited from differ- ent geographic regions throughout Germany. Their names and addresses were obtained from local registry offices (‘‘Ein- wohnermeldeamt’’) and from the Federal Administrative Office, using the Centenarian Graduation List recently issued by the German President of State. All potential participants were contacted by a letter in which the study was explained and permission was asked to send a questionnaire and a blood sampling kit. Probands were advised to consult their general practitioner for taking a blood sample and for help with filling out the questionnaire. A full socioeconomic, quality of life, and health status assessment was performed. Primary criteria for