Association of a polymorphic variant of the Werner helicase gene with myocardial infarction in a Japanese population
ABSTRACT 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.
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- "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). "
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 · 3.51 Impact Factor
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- "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). "
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.Experimental Gerontology 05/2002; 37(4):491-506. DOI:10.1016/S0531-5565(01)00227-3 · 3.53 Impact Factor
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- "In an initial study of the 1367Cys/Arg polymorphism in the Japanese population, we showed that homozygosity of Cys predicted an approximately 3-fold higher incidence of myocardial infarction than in normal control patients [Ye et al., 1997]. This result was subsequently confirmed by the independent Japanese study [Morita et al., 1999]. "
ABSTRACT: Werner syndrome (WS) is a progeroid syndrome caused by autosomal recessive null mutations at the WRN locus. The WRN gene encodes a nuclear protein of 180 kD that contains both exonuclease and helicase domains. WS patients develop various forms of arteriosclerosis, particularly atherosclerosis, and medial calcinosis. The most common cause of death in Caucasian subjects with WS is myocardial infarction. Previous studies have identified specific polymorphisms within WRN that may modulate the risk of atherosclerosis. Population studies of the 1074Leu/Phe and 1367Cys/Arg polymorphisms were undertaken to evaluate the role of WRN in atherogenesis. Frequencies of the 1074Leu/Phe polymorphisms in Finnish and Mexican populations revealed an age-dependent decline of 1074Phe/Phe genotype. In Mexican newborns, but not in Finnish newborns, the 1074Leu/Phe and 1367Cys/Arg polymorphisms were in linkage disequilibrium. Among coronary artery disease subjects, there was a tendency for the 1074Phe allele to be associated with coronary stenosis in a gene dose-dependent manner. Furthermore, the 1367Arg/Arg genotype predicted a lower degree of coronary artery occlusion, as measured by NV50, when compared to the 1367Cys/Cys or 1367Cys/Arg genotypes. However, these tendencies did not achieve statistical significance. Samples from Mexican patients with ischemic stroke showed a trend of haplotype frequencies different from that in a control group of Mexican adults. These data support the hypothesis that WRN may mediate not only WS, but may also modulate more common age-related disorders and, perhaps, a basic aging process. Am. J. Med. Genet. 95:374–380, 2000. © 2000 Wiley-Liss, Inc.American Journal of Medical Genetics 12/2000; 95(4):374 - 380. DOI:10.1002/1096-8628(20001211)95:4<374::AID-AJMG14>3.0.CO;2-4 · 3.23 Impact Factor