The Werner syndrome (WS) is a rare autosomal recessive progeroid syndrome characterized by the premature onset of multiple age-related disorders, including atherosclerosis, cancer, non-insulin-dependent diabetes mellitus (NIDDM), ocular cataracts and osteoporosis [Epstein et al., 1966]. The major cause of death (at a median age of 47) is myocardial infarction (MI) [Epstein et al., 1966]. The WS mutation involves a member (WRN) of the RecQ family of helicases and may perturb DNA replication, repair, recombination, transcription, or chromosomal segregation [Yu et al., 1996]. We now report data on 149 MI cases and age-matched controls suggesting that a polymorphic WRN variant is associated with increased risk for MI. Based on our data, homozygosity for a cysteine at amino acid 1367 (the most prevalent genotype) predicts a 2.78 times greater risk of MI (95% confidence intervals: 1.23 to 6.86). The variant was not significantly associated with NIDDM. The two alleles (cysteine vs. arginine) could influence helicase activity, turnover, macromolecular interactions or, alternatively, could be markers for haplotypes influencing WRN regulation or reflecting gene action at linked loci. However, given the caveats implicit in genetic association studies, it is imperative that the present results be replicated in independent populations.
"In addition, Bohr et al. , in the Baltimore Longitudinal Study of Aging, failed to show any influence of the WRN polymorphism on coronary artery disease. However, studies in Japanese populations found that patients homozygous for TT were at nearly threefold higher risk of myocardial infarct than the general population ; other researchers from countries other than Japan reported a similar risk for CT in their populations . CC homozygosity posed a lower risk [34,35] and also protected against the development of type 2 diabetes mellitus . "
[Show abstract][Hide abstract] ABSTRACT: Werner syndrome is an autosomal recessive disease of premature aging caused by a polymorphic C1367T mutation in the Werner (WRN) gene. Although there are differences between the pathobiology of normal aging and the phenotype of Werner syndrome, the clinical age-related changes are similar. The aim of the study was to investigate the incidence of the C1367T (rs1346044) polymorphism in patients with age-related cataract.
The study group consisted of 81 patients with senile cataract undergoing cataract extraction surgery. Data on age, sex, and medical history of microvascular disease and cancer were obtained from the medical files. Anterior lens capsule material was collected during surgery. DNA was extracted, amplified by polymerase chain reaction, and screened for the C1367T polymorphism in WRN using restriction enzymes followed by sequencing.
There were 33 male and 48 female patients of mean age 74.3+/-9 years. Genotypic frequencies were 67% for TT and 33% for TC. None of the patients had the CC genotype. Ten patients had a history of myocardial infarct, 8 cerebrovascular accident, and 8 various tumors. The distribution of these morbidities was similar in the two genotype groups.
The distribution of the C1367T WRN polymorphism in patients with senile cataract is similar to that in the normal population. Cataract formation in the elderly is not linked to a WRN mutation.
"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). "
[Show abstract][Hide abstract] ABSTRACT: Mutations in the WRN gene lead to the Werner syndrome (WS), which resembles premature aging. Here, we hypothesize that genetic variations 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 1,245 participants aged 85 years and older, with a total follow-up of 5,164 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.
Mechanisms of Ageing and Development 04/2006; 127(3):307-13. DOI:10.1016/j.mad.2005.11.005 · 3.40 Impact Factor
"Recently, it was reported that a polymorphic WRN variant c.4330T . C leading to a C1367R substitution has been associated with a resistance to myocardial function (Ye et al., 1997). In a subsequent study, it was observed that the rare 1367 Arg allele was threefold higher in North American and Finnish adult populations compared to the Japanese population (Castro et al., 1999). "
[Show abstract][Hide abstract] ABSTRACT: Werners syndrome is a disease of premature aging where the patients appear much older than their chronological age. The gene codes for a protein that is a helicase and an exonuclease, and recently we have learned about some of its protein interactions. These interactions are being discussed as they shed light on the molecular pathways in which Werner protein participates. Insight into these pathways brings insight into the aging process.
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