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 , 2 , 6

1 Department of Medicine and 2 Institute for Aging Research, Albert Einstein College of Medicine of Yeshiva University, New York, New York . 3 Section of Molecular Epidemiology, Leiden University Medical Center, The Netherlands . 4 Departments of Epidemiology and Population Health , 5 Systems and Computational Biology , and 6 Genetics, 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, 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 fi nd that the MTP CC genotype is signifi cantly overrepresented in centenarians and their offspring, as compared with controls ( p < .05). However, when we examined 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). Further- more, the M TP 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 M TP 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 fi ndings of Geesaman and colleagues ( 6 ) were confounded by popula- tion stratifi cation in control participants .

a lipid transfer protein found in the liver and intestine and 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 single nucleotide polymorphisms (SNPs) in the M TP 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 dis- eases, it was not surprising that MTP also surfaced as one of the fi rst genes linked to exceptional human longevity ( 6 ).

Because most humans die between ages 60 and 100 y ea rs, with fewer “ survivors ” populating each successive decade, one may assume that a monotonic trend (increase or decrease) in genotype prevalence with age suffi ces to discern poten- tial benefi cial 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 ), A POC3 (C C ) [rs2542052] ( 14 ), A dipoQ (d el/del APM1 +2019) [rs56354395] (1 5) , 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 popu- lations are carriers of some variants of deleterious genes, even at levels comparable to or greater than younger control groups ( 18 , 19 ).

U sing sibpair analysis on centenarians and their siblings, Puca and colleagues (7 ) performed the fi rst genomic screen- ing for exceptional human longevity and reported linkage with a region on chromosome 4. Fine mapping of the candi- date region uncovered two SNPs, Q95H [rs61733139] , and rs2866164 in the M TP gene ( 6 ). By comparing a population of exceptionally long-lived individuals residing in the United States (mean age 100.8 y ea rs) to a younger U.S. control cohort (mean age 38.6 y ea rs), it was found that the minor allele of SNP rs2866164 ( G) was the risk allele, as it was underrepresented in the long-lived population. However, several studies in other long-lived populations have since

questionnaire. All p articipants underwent a physical exami- nation and provided a blood sample. We performed i dentity by d escent analysis to exclude cryptic relatedness among control – probands and control – offspring. In addition, Affyme- trix 6.0 was used to classify Ashkenazi origin ( four grand- parents) of all participants by p r inciple c o mponent a n alysis. Informed written consent was obtained in accordance with the policy of the Committee on Clinical Investigation of the Albert Einstein College of Medicine.