The Frequency of 4 Common Polymorphisms in Nonagenarians, Centenarians, and Average Life Span Individuals

1 1,2 Kolovou, MD, PhD , Vana Kolovou, MSc , 1 1 Vasiliadis, MD, PhD , Vasiliki Giannakopoulou, MD , 3 4 Mihas, MSc, PhD , Helen Bilianou, MD , 5 1 Kollia, MSc , Evaggelia Papadopoulou, MSc, PhD 1 6 Marvaki, MD , Georgos Goumas, MD , 7 8 Kalogeropoulos, MD , Sotiria Limperi, MD, PHD , 9 1 Katsiki, MD, PhD , and Sophie Mavrogeni, MD, PhD

1 1,2 Kolovou, MD, PhD , Vana Kolovou, MSc , 1 1 Vasiliadis, MD, PhD , Vasiliki Giannakopoulou, MD 3 4 Mihas, MSc, PhD , Helen Bilianou, MD , 5 Kollia, MSc , Evaggelia Papadopoulou, MSc, PhD 1 6 Marvaki, MD , Georgos Goumas, MD , 7 8 Kalogeropoulos, MD , Sotiria Limperi, MD, PHD , 9 1 Katsiki, MD, PhD , and Sophie Mavrogeni, MD, PhD

Abstract

Single nucleotide polymorphisms of angiotensin-converting enzyme (ACE) such as rs1799752, nuclear factor kappa B (NFkB) such as rs28362491 and cholesteryl ester transport protein (CETP) such as rs708272 (TaqB1) and rs5882 (I405V) were evaluated in nonagenarians, centenarians, and average life span individuals (controls). The study population (n ¼ 307; 190 nonagenarians, 12 centenarians and 105 middle-aged controls) was genotyped for ACE, NFkB, and CETP genetic variants. The age of nonagenarian and centenarian group ranged between 90 and 111 years; centenarians and controls age ranged from 99 to 111, and from 18 to 80 years, respectively. The I carriers of ACE I/D gene were fewer in nonagenarians compared to centenarians (37.6% vs 62.5%, P ¼ .016). The I carriers of ACE gene were more frequent in centenarians compared to controls (62% vs 41%, P ¼ .045). No differences in frequency of common NFkB and CETP genotypes between patients with exceptional longevity and middle-aged patients were observed.

Keywords

centenarians, single nucleotide polymorphisms, angiotensin-converting enzyme, nuclear factor kappa B, choles- ester transport protein

Introduction

During the last decades, the survival of elderly people improved significantly and thus the centenarians were becom- ing the fastest growing population group.1 Human life span is dependent on environmental, genetic, and accidental factors.2 Genetic factors contribute to the variation of human life span by around 25% which is believed to be more profound after 85 years of age.3 According to the genetic influence to longev- ity, the nonagenarians and centenarians may represent a partic- ularly informative study population in the search for traits of genes associated with longevity. Several research teams are working on genes involved in oxidative stress, lipid and glucose metabolism, inflammation, DNA damage and repair, axis of growth hormone and insulin-like growth factor, and others.4 The results are still conflicting and it may be suggested that the combination of numerous fixed genetic variants will be necessary for someone to achieve exceptional longevity.

Department, Onassis Cardiac Surgery Center Athens, Greece Immunology Laboratory, Onassis Cardiac Surgery Center

Corresponding Author:

Genovefa Kolovou, Cardiology Department, Onassis Cardiac Surgery Center, 356 Sygrou Ave 176 74 Athens, Greece. Email: genovefa@kolovou.com

association studies published by the National Cancer Institute- National Human Genome Research Institute (NCI-NHGRI) Working Group on Replication in Association Studies14 indicat- ing time period and location of participant recruitment, success rate for DNA acquisition, internal control samples (from the same DNA), and sample tracking methods.

Numerous hypotheses have been proposed to explain the biological mechanisms of longevity.5 Today’s centenarians have survived nearly the double their life expectancy at birth (the life expectancy in 1912 was 51 years for men and 56 years for women) and have often been spared from age-related diseases, specifically cardiovascular disease, Alzheimer disease, diabetes mellitus, and cancer.6

Written consent was obtained from each participant. The study protocol was approved by the institutional ethics commit- tee (Onassis Cardiac Surgery Center, Athens, Greece) and was in accordance with the Declaration of Helsinki for Human Research of 1974 (last modified in 2000). All study participants were of Caucasian origin and descent for (cid:2)3 generations.

Because of the strong heritability of those survivals, we are investigating the gene variants that could explain the extended life of nonagenarians and centenarians compared to middle- aged individuals in the Hellenic population.

The cholesteryl ester transport protein (CETP) may have pro- or antiatherogenic properties depending upon the lipid- metabolic setting.7 High-density lipoprotein (HDL) particles are influenced by CETP activity; CETP promotes the exchange of cholesteryl esters for triglycerides (TGs) between HDL par- ticles and TG-rich lipoproteins.8 Ordovas et al9 suggested that increased HDL cholesterol levels resulting from lower CETP activity seems to be associated with a lower risk of coronary heart disease in men.

Control Group (n ¼ 105). The inclusion criteria for this group were (1) age 18 to <80 years, (2) no personal history of coronary artery disease, diabetes mellitus, thyroid and liver disease, high alcohol consumption, professional athleticism and any chronic disease, and (3) no family history of longevity ((cid:2)90 years).

Nonagenarians and Centenarians (n ¼ 202). The inclusion criteria for these groups were the age (cid:2)90 to 98 years in Non- agenarians and (cid:2)99 years in centenarians. No other inclusion and exclusion criteria were applied.