Preliminary Evidence of a Genetic Association Between Chromosome 9p21.3 and Human Longevity

Enzo Emanuele,1 Jacopo M. Fontana,2 Piercarlo Minoretti,3 and Diego

Abstract

Background: Emerging evidence suggests that there is a significant genetic component to human longevity. One or more genetic variants located on chromosome 9p21.3 and tagged by the single-nucleotide polymorphism (SNP) rs1333049 (G=C) are major risk factors for age-related disorders, including acute myocardial infarction (AMI), stroke, and dementia. We hypothesized that this locus may have widespread effects on aging phenotypes and, as such, influences the ability to achieve a long and healthy life. Aim: The aim of this study was to assess whether the rs1333049 polymorphism is associated with human

Emerging evidence suggests that there is a significant genetic component to human longevity. One genetic variants located on chromosome 9p21.3 and tagged by the single-nucleotide polymorphism (G=C) are major risk factors for age-related disorders, including acute myocardial infarction and dementia. We hypothesized that this locus may have widespread effects on aging phenotypes and, influences the ability to achieve a long and healthy life. The aim of this study was to assess whether the rs1333049 polymorphism is associated with We tested the rs1333049 polymorphism in a sample of 80 healthy centenarians (39 men and 41 100–104), 218 patients younger than 40 who experienced an AMI, and a control group of 258 healthy matched to AMI patients for age and sex. The frequency of the C allele of rs1333049 was significantly lower in centenarians compared to whereas AMI patients showed a higher frequency. After adjustment for gender and traditional factors, the C allele of rs1333049 remained significantly associated with a reduced likelihood to reach Odds ratio (OR) 0.64, 95% confidence interval (CI) 0.39–0.89, p < 0.01. Our data suggest that the rs1333049 polymorphism at 9p21.3 may influence successful possibly by modulating the risk of age-related disorders.

Results: The frequency of the C allele of rs1333049 was significantly lower in centenarians compared to young controls, whereas AMI patients showed a higher frequency. After adjustment for gender and traditional vascular risk factors, the C allele of rs1333049 remained significantly associated with a reduced likelihood to reach lon- gevity: Odds ratio (OR) 0.64, 95% confidence interval (CI) 0.39–0.89, p < 0.01. Conclusions: Our data suggest that the rs1333049 polymorphism at 9p21.3 may influence successful human longevity, possibly by modulating the risk of age-related disorders.

Background

with vascular dementia and late-onset Alzheimer disease.14 Of note, commercial DNA tests for this locus are already available and directly marketed to the general public.18

is a marked delay or absence from major age-related dis- eases and disabilities, including acute myocardial infarction (AMI), stroke, and dementia, which, respectively, are the first, the third, and the fourth largest causes of mortality in Western countries.1–3 Genetic influences account for about a quarter of the variance in adult human life span,4,5 and it is likely that longevity-predisposing genetic polymorphisms may allow carriers to escape from these leading causes of mortality.6

If the high-risk C allele of rs1333049 tracks with disability and age-related disorders, then there should be a reduced frequency of CC homozygotes in the oldest old. Therefore, we sought to evaluate whether the rs1333049 polymorphism could be associated with longevity in humans. In line with previous studies,16,17 we decided to focus only on this genetic marker because the polymorphisms rs1333039, rs10757274, and rs10757278 on chromosome 9p21.3 identified as risk loci for cardiovascular disease in previous studies are in tight linkage disequilibrium (r2 > 0.9), and their associations with a selected phenotype are generally identical.19

The recent identification of a novel susceptibility locus of approximately 100kbp on chromosome 9p21.3 that may be linked to a significantly higher risk for age-related disorders has generated great interest.7–14 Specifically, a common ge- netic variant (tagged by rs1333049, G=C) in this genomic region has been associated with coronary artery disease (CAD),15 prevalent carotid atherosclerosis and incident car- diovascular disease,16 and AMI.12,17 Furthermore, there is preliminary evidence that this polymorphism is associated

Methods

Study participants

We tested the rs1333049 polymorphism in a sample of 80 centenarians (39 men and 41 women, aged 100–104;

1Department of Health Sciences, and 4Department of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia, Italy. 2Department of Physiology, Section of Human Physiology, University of Pavia, Pavia, Italy. 3Alessandro Manzoni Hospital, Lecco, Italy.