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

1,2 Genovefa Kolovou, MD, PhD, Vana Kolovou, MSc, 1,2 Vasiliadis, MD, PhD, Vasiliki Giannakopoulou, MD, 3,4 Mihas, MSc, PhD, Helen Bilianou, MD, 5 Kollia, MSc, Evaggelia Papadopoulou, MSc, PhD 6 Marvaki, MD , Georgos Goumas, MD , 7 8 Kalogeropoulos, MD , Sotiria Limperi, MD, PhD , 9 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 = 307; 190 nonagenarians; 12 centenarians and 105 middle-aged controls) was genotyped for ACE; NFkB; and CETP genetic variants. The age of the 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 = 0.016). The I carriers of ACE gene were more frequent in centenarians compared to controls (62% vs. 41%, P = 0.045). 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, cholesteryl ester transport protein

Introduction

During the last decades, the survival of elderly people has improved significantly, and thus the centenarians have become the fastest growing population group.1 Human life span depends 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 on longevity, nonagenarians and centenarians may represent a particularly 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.

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 particles 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 = 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 = 202). The inclusion criteria for these groups were the age (cid:2)90 to 98 years in Nonagenarians and (cid:2)99 years in centenarians. No other inclusion and exclusion criteria were applied.

The renin-angiotensin-aldosterone system (RAAS) also plays a significant role in the maintenance of cardiovascular homeostasis. The angiotensin-converting enzyme (ACE) is an important gene of the RAAS that has been evaluated in the pathogenesis of hypertension, coronary artery disease, heart failure, and recently of longevity. Furthermore, the nuclear factor kappa B (NFkB) gene is a regulator of the genes that encode cytokines and cell-ad43.9% had DD; 117 had 38.4% NFkB[-94ins/delATTG (W/D)], with ins/ins at 106 (47.7%), ins/del at 94 (42.3%), and del/del at 22 (9.9%). The percentage of participants aged below 80 was <80%. The age range was between 90 and 111 years, with a median of 93 + 4 years, while the control group had a median age of 60 + 21 years. The study analyzed three SNPs in four candidate genes in pathways related to lipoprotein metabolism, hypertension, and stress response, all closely related to aging. The I carriers of ACE gene were fewer in nonagenarians compared to centenarians and more frequent in centenarians compared to controls. Genotypic and allele frequencies did not differ by gender in any of the study groups. No adjustment for inflation of type I error due to multiple comparisons was made as a result of their relatively low number.

The I carriers of ACE I/D gene were fewer in nonagenarians compared to centenarians (37.6% vs 62.5%, P .016). Similarly, the I carriers of ACE gene were more frequent in centenarians compared to controls (62% vs 41%, P .045). There were no significant differences in genotypes/allele frequency of both CETP gene polymorphisms between groups.

According to NFkB gene polymorphism, our study did not find any difference in genotypes/allele frequency between groups. Some studies have suggested that NFkB gene polymorphism is involved in aging.