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, 2 1 Rudi G. J. Westendorp, and P. Eline Slagboom

1Molecular Epidemiology, 2Gerontology and Geriatrics, Department of General Internal Medicine, and 3Medical 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 to 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 (cid:1)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 also prospective analyses using the longitudinal data. We found neither evidence for linkage at 4q25 nor 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.

in long-lived sibling pairs. In this approach, no assumptions are made with respect to the inheritance pattern of the trait and no control group for the nonagenarian participants is required. Puca and colleagues (7) measured 400 micro- satellite markers with 10-cM spacing in 308 individuals belonging to 137 sibships, of which the oldest sibling was at least 98 years old and other siblings were older than either 91 years (if male) or 95 years (if female). Chromosome 4q25 was found to be linked with the exceptional longevity phenotype, and after fine mapping of this region, a maximum Logarithm of odds (LOD) score of 3.65 was obtained at a 12-cM region containing approximately 50 genes. To investigate which of the 50 genes in the linkage region might be responsible for the remarkable linkage result, the whole region was saturated with single-nucleotide poly- morphisms (SNPs) (8) to test for association with longevity. A two-SNP haplotype in the microsomal transfer protein (MTP) gene was found to be associated with longevity, marked by the SNPs rs2866164 and Q95H. Variation in this gene has previously been associated with plasma levels of low-density lipoprotein (LDL) cholesterol (9–12), lipopro- tein particle size (13), obesity (14), and insulin levels (14). However, contradictory results have also been published (15–17). It is possible that the MTP gene is involved in cardiovascular risk by influencing lipid metabolism, and thus may contribute to longevity.

and centenarians, who represent the extreme tail of the distribution of human life span, have a history of aging slowly, and either markedly delay or escape age-associated diseases (1,2). Influencing the human life span and reaching old age in good health remains a wish for many people. Human variation in life span 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 for cancer). Environmental factors are hard to study in humans. Current genetic research of longevity aims to identify the genes involved in the ability to become long-lived from the perspective that such may indicate the major relevant pathways of human life-span 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 (3). Furthermore, the study of the comprehensive population-based genealogy database of the Icelandic population shows that a clear familial component is present in longevity (4). This hereditary component could represent shared environmental factors as well as shared genetic factors. From twin studies, it was estimated that ap- proximately 25% of the variation in life span is contrib- utable to genetic variation (5,6). 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 vet- erans (18), it can be questioned whether this locus is of im- portance 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