of Relationship Between MTTP Haplotypes and Longevity

1 2 3 4 Matt J. Neville, Robert Clarke, John Grimley Evans, David C. Rubinsztein, and Fredrik Karpe

1Oxford Centre for Diabetes, Endocrinology and Metabolism, 2Clinical Trial Service Unit, and 3Division of Clinical Geratology, Nuffield Department of Clinical Medicine, University of Oxford, United Kingdom. 4Department of Medical Genetics, Cambridge Institute for Medical Research,

Background. Polymorphisms for the microsomal triglyceride transfer protein (MTTP) gene have been associated with longevity and with lower risk for cardiovascular mortality. However, the association of MTTP with longevity has been contested in a large German collection of nonagenarians and centenarians.

Methods. We made a detailed characterization of MTTP haplotype carrier status in a cohort of 1398 old men and women (mean age 78 years) and a population-based cohort (n¼777) of younger controls (mean age 40 years) in Oxford, England.

Results. There were no significant differences in haplotypes for MTTP gene between the younger and older age

Conclusion. This study, which adopted a more detailed genetic analysis of the MTTP gene in a large case–control study of older people provides reliable evidence against any significant association of the MTTP gene with longevity.

Recently, Nebel and colleagues (8) were unable to verify any association between MTTP haplotypes and longevity in a collection of 1589 nonagenarians and centenarians with appropriately matched controls using three single-nucleotide polymorphisms (SNPs) to form haplotypes in MTTP gene (8). They argued that the initial observation indicating linkage of the MTTP gene with longevity may have been flawed by inadequate matching of the control sample.

of the reported associations of genes with longevity in humans have not been replicated. The apolipoprotein E (APOE) gene, of which the e4 variant predisposes to both Alzheimer’s disease (1,2) and cardio- vascular disease (3), is one of the few genes to be consistently associated with longevity. Since the candidate gene approach is unlikely to provide novel suggestions for longevity genes, it was of great interest that a region on chromosome 4 associated with longevity was implicated in a genome-wide scan (4) of Caucasian individuals living in North America. The gene of interest on chromosome 4 was later identified as MTTP (microsomal triglyceride transfer protein gene) by fine-mapping the region of interest (5).

The MTTP gene is highly heterogeneous, and we have already shown that determination of haplotype structure based on either two, as in the report by Geesaman and col- leagues, or three SNPs, as used by Nebel and colleagues, would provide a rather restricted view of the complex ge- netic variability in the MTTP gene. We have therefore deter- mined the haplotype frequencies, based on 11 SNPs, in an Oxford-based collection of 1451 old people and compared this with 777 population-based controls in the age range 30–50 years to assess possible associations of the MTTP gene with longevity.

potentially related to cardiovascular disease by regulation of the plasma concentration of low-density lipoprotein choles- terol (6). However, although we recently observed an association between certain MTTP genetic variants and risk of cardiovascular disease in the West of Scotland Pro- spective Study (WOSCOPS) (7), this association appeared to be unrelated to plasma low-density lipoprotein cholesterol concentrations. Interestingly, one of the polymorphisms ex- amined in the haplotype-based identification of the MTTP gene for longevity (5), rs2866164, is in complete linkage disequilibrium (LD) with the MTTP-493G/T variant as- sessed in the WOSCOPS. It, therefore, seemed plausible that the increased risk of nonfatal and fatal cardiovascular disease associated with carriers of the MTTP-493T variant might explain the association of longevity with carriers of the MTTP-493G variant.

M ETHODS

Populations

The DNA bank of older people derived from the Oxford Healthy Aging Project (9) comprises a random sample of 2740 people aged 65 years and older, who resided in the city of Oxford, England, when first examined between 1991 and 1994. The sample was drawn from general practice registers to provide equal numbers of participants aged 65–74 years

Table 1. Allele Frequencies for the MTTP Gene in Younger and Older Age Populations

Statistics

Differences in genotype and haplotype frequencies between the older and younger populations were assessed by means of a chi-square test estimated using SPSS (14.0). A power calculation was made using the software Quanto, version 0.5.5, available at http://hydra.usc.edu/GxE/ using an allele frequency of 0.25 in a log-additive model and a case/control ratio of 1:0.5 (this corresponds to a multiplica- tive, i.e., allele-wise model as actually tested). The relative risks ranged from 1.1 to 1.5, and the power from 70% to 95%, to obtain a thorough evaluation of power. With these assumptions, this study has ;70% power to detect an effect size as small as 1.2 and .95% power to detect an effect size of 1.3.

Younger Population Older Populations SNP No. % No. % Chi-Square p Value 128I 1162 (75%) 2051 (73%) NS 128T 392 (25%) 745 (27%) NS 95Q 1463 (94%) 2663 (93%) NS 95H 91 (6%) 187 (7%) NS

Note: MTTP ¼ Microsomal triglyceride transfer protein; SNP ¼ single- nucleotide polymorphism; NS ¼ not significant.