Mechanisms of Ageing and Development 127 (2006) 307-313 www.elsevier.com/locate/mechagedev 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 

a Department of Gerontology and Geriatrics C2-R, Leiden University Medical Center (LUMC), P.O. Box 9600, 2300 RC Leiden, The Netherlands 

b Department of Biotechnology, Institute of Molecular and Cell Biology, Tartu University, Tartu, Estonia 

c Section 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: Polymorphisms in the WRN gene have been associated with Werner Syndrome (WS), a segmental progeroid disorder with symptoms resembling premature aging. This study aimed to investigate whether polymorphisms in the WRN gene also influence aging trajectories and survival in the general population. The impact of i1-C/T, L1074F and C1367R polymorphisms on cardiovascular pathologies, cognitive performance and all-cause mortality risks were assessed in the population-based Leiden 85-plus Study. Results showed that the studied polymorphisms did not influence aging trajectories or survival in the population at large.

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

1. Introduction 

Werner Syndrome (WS) is a segmental progeroid disorder with an autosomal recessive pattern of inheritance. Patients with WS display symptoms resembling premature aging, including diabetes, osteoporosis, vascular diseases and high incidence of malignant neoplasms. Death usually occurs before the age of 50 years due to cancer or atherosclerosis. 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 hypothesized that polymorphisms in the WRN gene 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 a 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, whereas in Caucasians no associations with cardiovascular disease have been found. An i1-C/T polymorphism has been related to cognitive functioning, and for an L1074F SNP an age-dependent enrichment of the 1074L allele in Finnish and Mexican populations has been observed. 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 on the i1-C/T and L1074F polymorphisms on cardiovascular disease risks in elderly.

2. Materials and Methods 

The study was carried out in elderly participants aged 85 years and older using cross-sectional and prospective study designs. The i1-C/T (rs2725335) and C1367R (rs1346044) variations were genotyped using an Assay-by-Design (Applied Biosystems), while the L1074F (rs2725362) polymorphism was genotyped by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS), using the Sequenom MassARRAYtm methodology. 

The impact of the i1-C/T, L1074F and C1367R polymorphisms on cardiovascular pathologies, cognitive performance and all-cause and cause-specific mortalities were analyzed using logistic regression models and linear mixed models.

3. Results 

Results showed that the studied polymorphisms did not influence aging trajectories or survival in the population at large. At baseline, the risks of myocardial infarction, myocardial ischemia, intermittent claudication, arterial surgery and stroke 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. Mortality risks were similar between the different genotype carriers of the i1-C/T, L1074F and C1367R polymorphisms.

4. Discussion 

In conclusion, this study suggests that the i1-C/T, L1074F and C1367R polymorphisms in the WRN gene do not influence aging trajectories or survival in the population at large. These findings provide important insights into the role ofCognition during the follow-up was adjusted for sex and level of education. Mortality was estimated using the Kaplan-Meier method, followed by the calculation of sex-adjusted mortality risks and 95% confidence intervals (CI) for all-cause, cardiovascular, and cancer mortality with the Cox proportional hazard model, using left censoring to correct for the delayed entry into the risk set according to age. For each polymorphism, hazard ratios (HR) were calculated using common allele homozygotes as the referent group. All analyses were performed with SPSS statistical software, Version 12.0 (Chicago, IL, USA), except for the mortality analyses, which were performed with STATA software, Version 9.0 (TX, USA).

2. Subjects and methods

2.1. Study population