Mechanisms of Ageing and Development 127 (2006) 307–313

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Impact of genetic variations in the WRN gene on age related pathologies and mortality

Maris Kuningas , P. Eline Slagboom , Rudi G.J. Westendorp , Diana van Heemst

aDepartment of Gerontology and Geriatrics C2-R, Leiden University Medical Center (LUMC), P.O. Box 9600, 2300 RC Leiden, The bDepartment of Biotechnology, Institute of Molecular and Cell Biology, Tartu University, Tartu, Estonia cSection of Molecular Epidemiology, Department of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands

Received 10 October 2005; received in revised form 10 November 2005; accepted 15 November 2005 Available online 6 January 2006

Abstract

in the WRN gene may also influence aging-trajectories in the population at large. To test this hypothesis, we assessed the impact of the i1-C/T, L1074F and C1367R polymorphisms in the WRN gene on the occurrence of cardiovascular pathologies, on cognitive performance and on the risks of all-cause, cardiovascular and cancer mortalities in the population-based Leiden 85-plus Study. This prospective follow-up study includes 1245 participants aged 85 years and older, with a total follow-up of 5164 person-years. At baseline the risks of myocardial infarction, myocardial ischemia, intermittent claudication, arterial surgery and stroke dependent on the i1-C/T, L1074F and C1367R polymorphisms, did not vary between the different genotypes. Also no differences in cognitive functioning were observed, except for attention, where carriers of the 1367R allele performed worse compared to the 1367C homozygotes (94.2 (4.35) versus 84.8 (1.84), p = 0.04). Mortality risks, calculated separately for all SNPs, were similar between the different genotype carriers of the i1-C/T, L1074F and C1367R polymorphisms, showing no evidence of altered survival. In conclusion, the i1-C/T, L1074F and C1367R polymorphisms in the WRN gene do not influence the aging-trajectories and survival in the population at large.

Keywords: WRN gene; i1-C/T, L1074F and C1367R polymorphisms; Cohort

1. Introduction

and exonuclease activities (Liu et al., 1999; Morozov et al., 1997; Mushegian et al., 1997). Evidence from several studies suggests that this protein is involved in the response to DNA damage during replication, recombination and transcription processes (Balajee et al., 1999; Webb et al., 1996). WRN is active in unwinding alternate DNA structures, such as DNA– RNA hybrids, triplexes and tetraplexes that may otherwise cause genomic instability (for review Bachrati and Hickson, 2003; Opresko et al., 2003). Genomic instability along with accumulation of damage and cellular senescence is commonly seen in WS cells (for review Brosh and Bohr, 2002; Macario and Conway, 2002). Senescent cells go through alterations in gene expression patterns, which in turn have been shown to underpin several pathologies in tissues such as skin and vasculature (Minamino et al., 2004; Shelton et al., 1999). These processes are likely to lead to the disease pathologies seen in WS patients, and also during aging in the population at large (Bird et al., 2003; Hasty et al., 2003). Since WS resembles

Werner syndrome (WS) is a segmental progeroid disorder with an autosomal recessive pattern of inheritance. Patients with WS exhibit a number of symptoms that resemble premature aging. Characteristic clinical features of the syndrome include diabetes, osteoporosis, vascular diseases and high incidence of malignant neoplasms. Death usually occurs before the age of 50 years due to cancer or atherosclerosis (Martin, 1978; Salk, 1982). WS is caused by loss-of-function mutations in the WRN gene. Since mutations in the WRN gene lead to accelerated aging, it has been reasoned that polymorphisms in the WRN gene may also associate with age related pathologies and thus influence aging in the population at large.

* Corresponding author. Tel.: +31 71 5266640; fax: +31 71 5248159. E-mail address: D.van_Heemst@lumc.nl (D. van Heemst).

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may also modulate the course of aging in the population at large and play a role in the sensitivity or resistance to the development of age related disorders. Only few studies have addressed this question, with contradictory results. Studies in Japanese have shown that a C1367R variation in the WRN gene is associated with myocardial infarction (Morita et al., 1999; Ye et al., 1997), whereas in Caucasians no associations with cardiovascular disease have been found (Bohr et al., 2004; Castro et al., 1999). An i1-C/T polymorphism, on the other hand, has been related with cognitive functioning (Bendixen et al., 2004), and for a L1074F SNP an age-dependent enrichment of the 1074L allele in Finnish and Mexican populations has been observed (Castro et al., 2000). The latter result suggests a beneficial effect on survival. These associations have been found in separate studies and to date there are no data on the influence of the C1367R polymorphism on cognitive function and survival, and no information of the i1-C/T and L1074F polymorphisms on cardiovascular disease risks in elderly.

The prevalence and number of cardiovascular pathologies were obtained from the participants’ general practitioner or nursing home physician. In addition, electrocardiograms were recorded on a Siemens Siccard 440 and transmitted by telephone to the ECG Core Lab in Glasgow for automated Minnesota coding (Macfarlane and Latif, 1996). Cardiovascular pathologies were classified as: myocardial infarction, myocardial ischemia, intermittent claudication, arterial surgery and stroke (van Exel et al., 2002).

2.3. Cognitive function tests in cohort ’97