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Increased frequency of the 2437T allele of the heat shock protein 70-Hom gene in an aged Irish population

a,b,* a,c a d Owen A. Ross, Martin D. Curran, Karen A. Crum, I. Maeve Rea, Yvonne A. Barnett

a,b,c Derek Middleton

a Northern Ireland Regional Histocompatibility and Immunogenetics Laboratory, Blood Transfusion Building, City Hospital, Belfast,

b School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, UK

c School of Biology and Biochemistry, Queen's University of Belfast, Belfast, Northern Ireland, UK

d Department of Geriatric Medicine, Queen's University of Belfast, Belfast, Northern Ireland, UK

Received 16 August 2002; received in revised form 28 November 2002; accepted 9 January 2003

Abstract

The frequency of the functional polymorphism, T2437C transversion (Met!Thr), in the HSP70-Hom gene was investigated within a healthy aged Irish population using oligonucleotide probes. The 2437T polymorphic nucleotide was observed to increase in the elderly, although not attaining statistical significance. The TT genotype was observed to be significantly increased within the Irish aged population p < 0.03; while conversely the TC genotype was significantly decreased in the aged subjects p < 0.01: These findings would support the theory that the change from a Met (non-polar and hydrophobic) residue to a Thr (polar and neutral) residue may disrupt the peptide-binding specificity of HSP70-Hom and have an effect on its functional efficiency. One postulates that the highly significant p-value obtained for the TC genotype may infer that the presence of both the T and C allele (heterozygosity) resulting in the generation of two different HSP70-Hom protein species may negatively influence longevity. q 2003 Elsevier Science Inc. All rights reserved.

Keywords: Heat shock protein; HSP70-Hom; Polymorphism and ageing

1. Introduction

DNA and proteins have all been thought to be protected by HSPs. It has also been postulated that heat shock may increase the expression or the activity of antioxidant enzymes, catalase or superoxide dismutase (Polla et al., 1996). Members of the 70 kDa heat shock protein family (HSP70) are consistently associated with defences against conditions involving oxidative stress such as ischemia, inflammation, and the ageing process (Jac- quier-Sarlin et al., 1994; Plumier et al., 1995; Wheeler et al., 1995).

Heat shock proteins (HSPs) are a group of conserved proteins that are induced in both prokaryotes and eukaryotes by elevated temperatures or a variety of cellular stresses. The cells reduce their overall rates of gene transcription and translation, and for a short period of time produce HSPs. HSPs act as molecular chaperones by binding to unfolded or misfolded proteins, promoting either correct refolding or proteolytic degradation (Jindal, 1996; Mathew and Morimoto, 1998; Soti and Csermely, 2000; Verbeke et al., 2001).

Different model systems have demonstrated that the induction of HSPs, particularly HSP70, declines in response to heat shock with ageing, therefore rendering the organism more vulnerable to stress damage (Favatier et al., 1997; Rea et al., 2001). Transgenic studies in Drosophila melanogaster have demonstrated an extension in normal lifespan when HSP70 is overexpressed (Tatar et al., 1997; Silbermann and Tatar, 2000). Thus any polymorphism that results in the alteration of qualitative or quantitative HSP70 expression could cause a differential sensitivity to stresses and affect longevity.

2. Materials and methods

2.1. Subjects