Experimental Gerontology 39 (2004) 1109–1114

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Interleukin 6 2 174 G/C promoter gene polymorphism in centenarians: no evidence of association with human longevity or interaction with apolipoprotein E alleles

Vincenzo , Alessia , Anna M. , Sabrina b b b b A. Capurso , Cosimo Semeraro , Antonio Capurso , Francesco Panza

aDepartment of Geriatrics-University of Foggia, Ospedali Riuniti Viale L. Pinto, 71100 Foggia, Italy bDepartment of Geriatrics, Center for Aging Brain, Memory Unit, University of Bari, Bari, Italy

Received 14 January 2004; received in revised form 10 March 2004; accepted 25 March 2004

Available online 20 April 2004

Abstract

The C allele at position 2174 in the promoter of the interleukin 6 (IL-6) gene has been associated with reduced gene expression and reduced plasma levels of IL-6. Given that IL-6 tracks with functional disability and age-related diseases, there may be attrition or reduction in the frequency of the homozygous subjects, who produce higher IL-6 serum levels, in older survivors in a population. In fact, a marked reduction of the IL-6*G/*G genotype was recently demonstrated in male though not female Italian centenarians compared with younger age groups. First aim of the present study was to investigate whether there was evidence of an association among IL-6 2174 G/C promoter polymorphism and extreme longevity in a population of 81 centenarians compared with a control group of 122 middle-aged healthy subjects (mean age: 51 ^ 18 SD; range: 19–73 years), from Apulia (Southern Italy). Secondly, we also tested possible interaction of apolipoprotein E (APOE) alleles with the IL-6 2174 G/C promoter polymorphism in view of our recent findings for reduced APOE 14 allele in centenarians. No differences have been found in the IL-6 2174 G/C promoter allele and genotype frequencies between centenarians and controls nor was there any observed interaction with APOE alleles that are also reputed to be linked to longevity. Regional genetic differences in conjunction with differing environmental factors may explain in part previous results suggesting a role of this polymorphism in longevity. q 2004 Elsevier Inc. All rights reserved.

Keywords: Interleukin-6; Apolipoprotein E; Centenarians; Longevity

1. Introduction

Ferrucci et al., 1999; Ershler and Keller, 2000). Bonafe` et al. found that subjects who are genetically predisposed to produce high levels of IL-6, i.e. IL-6*G/*G homozygous men, have a reduced capacity to reach the extreme longevity. In fact, they noted a marked reduction of the IL-6*G/*G genotype in male though not female Italian centenarians compared with elderly (60–80 years) and long-lived (81–99 years) subjects. On the other hand, they found that the age-related increase of IL-6 serum levels in women was independent of the 2174 G/C promoter polymorphism (Bonafe` et al., 2001). Furthermore, Olivieri et al. found that cultured peripheral blood mononuclear cells (PBMC) from C allele carrier individuals produced smaller amount of IL-6 than non-carriers and that IL-6 production by PBMC in vitro increased with age in C allele carriers but not in non-carriers. They also found that C allele carriers

The interleukin 6 (IL-6) gene in humans is located in the short arm of chromosome 7 (7p21) and has a 2174 G/C polymorphism in its promoter region. Fishman et al. (1998) reported that the IL-6 2174 G/C promoter polymorphism is associated with reduced IL-6 gene expression and also with reduced levels of IL-6 plasma levels. An age-related increase of IL-6 concentration has been found in serum, plasma and mononuclear blood cell culture among elderly people and centenarians (Fagiolo et al., 1993; Baggio et al., 1998). Recent population-based studies identified among elderly the magnitude of IL-6 serum levels as a predictor of

E-mail address: c.capurso@unifg.it (C. Capurso).

C. Capurso et al. / Experimental Gerontology 39 (2004) 1109–1114

had lower plasma levels of IL-6 than non-carriers, but this phenomenon was significant only in men (Olivieri et al., 2002). In recent studies, subjects carrying the G allele showed increased risk of Alzheimer’s disease (AD) (Pola et al., 2002a), multi-infarct dementia (MID) (Pola et al., 2002b), peripheral artery occlusive disease (PAOD) (Flex et al., 2002), asymptomatic carotid artery atherosclerosis quantified as increased intima-media thickness by high- resolution ultrasonography (Rauramaa et al., 2000), and longer stays in the hospital and in the intensive care unit after surgical coronary revascularization (Burzotta et al., 2001). Finally, in subjects under pravastatin treatment in the West of Scotland Coronary Prevention Study (WOSCOPS), the IL-6*C*/*C genotype was associated with a lower risk of coronary artery disease (CAD) (Basso et al., 2002).

severe functional limitations. The group of middle-aged adults included 122 healthy subjects (mean age: 51 ^ 18 SD; range: 19–73 years; 78 women and 44 men). These two groups had the same geographical origin and were sex- matched, reflecting the sex differential in longevity in Italy (Capurso et al., 1997). The study protocol received the approval of the Ethical Committee of the University of Bari. Informed consent was obtained from all subjects or their relatives.