Distinguishing Between Longevity and Buffered-Deleterious Genotypes for Exceptional Human Longevity: The Case of the MTP Gene

Derek M. Huffman,1,2 Joris Deelen,3 Kenny Ye,4 Aviv Bergman,5 Eline P. Slagboom,3 Nir Barzilai,1,2,6 and Gil Atzmon1,2,6

1Department of Medicine and 2Institute for Aging Research, Albert Einstein College of Medicine of Yeshiva University, New York, New York. 3Section of Molecular Epidemiology, Leiden University Medical Center, The Netherlands. 4Departments of Epidemiology and Population Health, 5Systems and Computational Biology, and 6Genetics, Albert Einstein College of Medicine of Yeshiva University, New York, New York. Downloaded from http://biomedgerontology.oxfordjournals.org/ at Ondokuz Mayis University on November 9, 2014.

Address correspondence to Gil Atzmon, PhD, Department of Medicine and Genetics, Institute for Aging Research, The Albert Einstein College of Medicine, Golding Building, Suite 502b, 1300 Morris Park Avenue, Bronx, NY 10461. Email: gatzmon@aecom.yu.edu

The single nucleotide polymorphism (SNP), rs2866164 in the MTP gene has been associated with human longevity but has not been validated by subsequent longevity studies. Using our population of Ashkenazi Jews we find that the MTP CC genotype is significantly overrepresented in centenarians and their offspring compared with controls (p < .05). However when we examined the MTP CC genotype frequency pattern with aging we observed a monotonic decline between ages 55-85 years followed by a dramatic enrichment after age 90 years forming a U-shape pattern (p < .05). Furthermore, the MTP CC genotype was buffered by three validated longevity genotypes (p < .05). This buffering effect was found to confer an enrichment of the MTP CC genotype in centenarians, whereas their absence in CC controls resulted in poorer survivorship (p < .05). Thus, we conclude that MTP CC is a buffered-deleterious genotype and that assessing genotype frequency across aging is essential for discerning longevity from buffered-deleterious genotypes.

Key Words: Genetics, Aging, Microsomal triglyceride transfer protein, Buffering mechanism.

Received October 26, 2011; Accepted March 1, 2012

Failed to detect any association between MTP and longevity (8-12) and have led several to conclude that the findings of Geesaman and colleagues (6) were confounded by population stratification in control participants. A lipid transfer protein found in the liver and intestine is necessary for the proper assembly of apolipoprotein B containing lipoproteins, very low-density lipoproteins (VLDL), and chylomicrons (1). Gene association studies have linked haplotypes and SNPs in the MTP gene with several diseases and risk factors including fatty liver disease (2), atherosclerotic risk factors (3), type 2 diabetes (4), and blood pressure (5). In light of its pleiotropic effects and harmful associations with many diseases, it was not surprising that MTP also surfaced as one of the first genes linked to exceptional human longevity (6).

Because most humans die between ages 60 and 100 years, with fewer survivors populating each successive decade, one may assume that a monotonic trend (increase or decrease) in genotype prevalence with age suffices to discern potential beneficial longevity genes from deleterious genes. In the absence of other diseases, such a trend could provide a unique opportunity for genetic analysis of longevity. Indeed, a monotonic increase in genotype frequency with aging suggests that it may confer a survival advantage, as we and others have shown for four genotypes: CETP (VV) [rs5882] (13), APOC3 (CC) [rs2542052] (14), AdipoQ (del/del APM1 +2019) [rs56354395] (15), and most recently, FOXO3a (16, 17). Conversely, it is expected that higher prevalence of harmful genotypes in a cohort will result in increasing rates of mortality in that cohort, leading to a monotonic decline in deleterious genotype frequency over time. However, it has been observed that centenarian populations are carriers of some variants of deleterious genes, even at levels comparable to or greater than younger control groups (18, 19).