The rs1333049 polymorphism on locus 9p21.3 and extreme longevity in Spanish and Japanese cohorts

Pinós & Noriyuki Fuku & Yolanda Cámara & Yasumichi Arai & Yukiko Abe & Rodríguez-Romo & Nuria Garatachea & Alejandro Santos-Lozano & Miro-Casas & Marisol Ruiz-Meana & Imanol Otaegui & Haruka Murakami & Miyachi & David Garcia-Dorado & Kunihiko Hinohara & Antoni L. Andreu Kimura & Nobuyoshi Hirose & Alejandro Lucia

Received: 22 April 2013 /Accepted: 10 October 2013 # American Aging Association 2013

Abstract The rs1333049 (G/C) polymorphism located on chromosome 9p21.3 is a candidate to influence extreme longevity owing to its association with age- related diseases, notably coronary artery disease (CAD). We compared allele/genotype distributions of rs1333049 in cases (centenarians) and controls (younger adults, without (healthy) or with CAD) in two n independent cohorts: Spanish (centenarians: =152, – n 128 women, 100 111 years; healthy controls: =343, n 212 women, age <50 years; CAD controls: =98, 32

women, age 65 years) and Japanese (centenarians: = – n 742, 623 women, 100 115 years; healthy controls: = n 920, 511 women, < 60 years; CAD controls: =395, 45 ≤ “ ” women, age 65 years). The frequency of the risk C- allele tended to be lower in Spanish centenarians P (47.0 %) than in their healthy (52.9 %, =0.088) or P CAD controls (55.1 %, =0.078), and significant P differences were found in genotype distributions ( = P 0.034 and =0.045), with a higher frequency of the GG genotype in cases than in both healthy and CAD

Tomàs Pinós and Noriyuki Fuku contributed equally.

Nobuyoshi Hirose and Alejandro Lucia share senior

N. Fuku

Y. Arai Y. Abe N. Hirose Department of Internal Medicine, Keio University School of Medicine,

E. Miro

Casas M. Ruiz

Meana I. Otaegui D. Garcia

Dorado Departamento de Cardiología, Hospital Universitari Vall d’Hebron, Barcelona, Spain

controls as well as a lower proportion of the CG genotype compared with healthy controls. In the Japanese cohort, the main finding was that the frequency of the C-allele did not differ between centenarians P (46.4 %) and healthy controls (47.3 %, =0.602), but it was significantly lower in the former than in CAD P controls (57.2 %, <0.001). Although more research is needed, the present and recent pioneer findings Rejuvenation Res – ( 13:23 26, 2010) suggest that the rs1333049 polymorphism could be among the genetic contributors to exceptional longevity in Southern European populations, albeit this association does not exist in the healthy (CAD-free) Japanese population.

the single nucleotide polymorphism (SNP) rs1333049 (G/C) located on chromosome 9p21.3, a locus outside of annotated genes that confers susceptibility to CAD and myocardial infarction as shown with recent genomewide scanning (McPherson 2010; Palomaki et al. 2010; Samani et al. 2007; Wellcome Trust Case Control Consortium 2007). This increased risk is independent of traditional risk factors including gender, age, obesity, smoking, hypertension, and hyperlipidemia (Schunkert et al. 2008). The C-allele (or the CC genotype) of rs1333049 has been associated with the risk or progression of CAD (Angelakopoulou et al. 2012; Bressler et al. 2010; Dandona et al. 2010; Ellis et al. 2010; Karvanen et al. 2009; McPherson 2010; Mendonca et al. 2011; Muendlein et al. 2009; ’ O Donnell et al. 2011; Palomaki et al. 2010; Plichart et al. 2012; Samani et al. 2009; Samani et al. 2007; Schunkert et al. 2008; Wellcome Trust Case Control Consortium 2007), and related disease phenotypes such as myocardial infarction (Buysschaert et al. 2010; Helgadottir et al. 2007; Koch et al. 2011; Scheffold et al. 2011; Shen et al. 2008b), atherosclerosis progression (Ye et al. 2008), peripheral arterial disease (Cluett et al. 2009), atherothrombotic manifestations (Arlestig and Rantapaa-Dahlqvist 2012), abdominal aortic aneurysm (Biros et al. 2010; Bown et al. 2008; Helgadottir et al. 2008), ischemic stroke (Karvanen et al. 2009; Smith et al. 2009), ’ vascular dementia (besides Alzheimer s disease) (Emanuele et al. 2011) or type 2 diabetes (Saxena et al. 2007). The aforementioned associations were obtained essentially in populations of Caucasian descent (North Americans or individuals from various European locations) and have been recently replicated in Asiatic cohorts, e.g., the rs1333049 SNP has been linked with CAD in Asian Indians (Maitra et al. 2009) and Japanese (Hinohara et al. 2008), with CAD (Wang et al. 2010), myocardial infarction (Peng et al. 2009), and coronary plaque progression in Chinese people (Yu et al. 2010) and with myocardial infarction in Japanese (Hiura et al. 2008), South Koreans (Shen et al. 2008a) and Pakistanis (Saleheen et al. 2010). In old Caucasians (>71 years), the C-allele has been

Centenarians are the survival tail of the population – (with a lifespan at least 15 20 years higher than the average westerner) and a model of healthy aging (Christensen et al. 2008). Such exceptional longevity is a partly heritable phenotype, with several candidate gene variants exerting a potential effect, e.g., polymorphisms associated with the risk of chronic, age-related diseases that are prominent causes of mortality among westerners, notably several types of cancer and coronary artery disease (CAD) (Ruiz et al.

Department of Health Promotion and Exercise, National Institute of Health and Nutrition, Tokyo, Japan

Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan

A. Lucia (*)

Universidad Europea and Instituto de Investigación Sanitaria Hospital

de Octubre (i+

), Madrid, Spain e-mail: alejandro.lucia@uem.es

In old Caucasians (>71 years), the C-allele has been associated with excess mortality independent of CAD risk factors (Dutta et al. 2011). A recent candidate– gene association study by Emanuele et al. reported a lower frequency of the risk C-allele of rs1333049 in 80 Italian centenarians compared to both healthy or