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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

aNorthern Ireland Regional Histocompatibility and Immunogenetics Laboratory, Blood Transfusion Building, City Hospital, Belfast, bSchool of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, UK cSchool of Biology and Biochemistry, Queens University of Belfast, Belfast, Northern Ireland, UK dDepartment of Geriatric Medicine, Queens 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 HSP 70-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 ðp ¼ 0:03Þ; while conversely the TC genotype was significantly decreased in the aged subjects ðp ¼ 0:01Þ: 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 HSP 70-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 the C allele (heterozygosity) resulting in the generation of two different HSP 70- 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 (HSP 70) 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 Mor- imoto, 1998; Soti and Csermely, 2000; Verbeke et al., 2001).

Different model systems have demonstrated that the induction of HSPs, particularly HSP 70, 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 HSP 70 is overexpressed (Tatar et al., 1997; Silbermann and Tatar, 2000). Thus any polymorphism that results in the alteration of qualitative

The exact molecular targets for HSP protection from oxidative stress is still unresolved but cell membranes,

* Corresponding author. Address: Northern Ireland Regional Histocompatibility and Immunogenetics Laboratory, Blood Transfusion Building, City Hospital, Belfast, Northern Ireland. Tel.: þ44-28-90263883; fax: þ44-28-90263880.

E-mail address: owenaross@hotmail.com (O.A. Ross).

0531-5565/03/$ - see front matter q 2003 Elsevier Science Inc. All rights reserved. doi:10.1016/S0531-5565(03)00006-8

Chromosome 6 short arm          centromeretelomere 6p21.3 telomereHLA RegionsClass Il Class Ill Class |4000 Kb _|HLA Class IH oH HHLA Class II LoL LAA AD DD BoC AP QR1000 Kb 2000 KbHLA Class IIIT:c HSP 70 N2 2 1 Hom a 1000Kb

Fig. 1. Three intronless genes coding for HSP 70 are located in the class III region of the HLA, 92 Kb telomeric to the C2 (complement 2) gene and 280 Kb centromeric to the TNF-a gene. The HSP 70-1 and 70-2 genes are 12 Kb apart and the HSP 70-Hom gene is located approximately 4 Kb telomeric to the HSP 70-1 gene. Nucleotide sequence analysis of HSP 70-1 and 70-2 genes has shown that they encode an identical protein product of 641 amino acids. HSP 70-Hom gene encodes a protein of 641 amino acids which has 90% sequence similarity with HSP 70-1 (Milner and Campbell, 1990).

or quantitative HSP 70 expression could cause a differential sensitivity to stresses and affect longevity.

gene in an Irish aged population in comparison to a cohort of younger controls.