Polymorphisms at the Werner locus: I. Newly identified polymorphisms, ethnic variability of 1367Cy/Arg, and its stability in a population of Finnish centenarians

Abstract

The Werner syndrome gene (WRN) encodes a novel helicase of 1,432 amino acids. Homozygous mutations, all of which result in the truncation of the protein, lead to Werner syndrome. However, little is known about the role of WRN in "normal" aging. We have identified four missense polymorphisms and four conservative polymorphsims in WRN gene. A single study showed that a polymorphism at amino acid 1367 Cys(TTG)/ Arg(CTG) is associated with a variation in risk of myocardial infarction among a Japanese population. The 1367 Cys/Arg polymorphism was examined during aging in three different populations: Finnish, Mexican, and North American. The frequencies of 1367 Cys were higher than those of 1367 Arg in all the populations examined, though the frequencies varied among populations. The frequency of the 1367 Arg allele, thought to be protective against myocardial infarction in a Japanese population, was approximately three times higher in the North American and Finnish adult populations. When newborns and centenarians were compared within the Finnish population, no differences were observed in the proportions of 1367 Cys/Arg across age groups. Within the Finnish population, we confirmed a significant decrease of the APOE epsilon2 allele and an increase in the epsilon4 allele in newborn infants compared with centenarians. Thus, unlike the APOE polymorphism, there is no evidence of an association of this WRN polymorphism with longevity.

SOD2polymorphisms: unmasking the effect of polymorphism on splicing

“…Comparisons of the distributions between two groups were tested by the modified Fisher exact test (two degrees of freedom) [30,31]. The latter was also examined with the standard Pearson chi-square test [32].…”

“…Total RNA was isolated using Trizol (Gibco BRL) and was reverse-transcribed with random hexamers with GeneAmp RNA PCR kit (Perkin Elmer Cetus Inc., Wellesley, MA) following the manufacturer's instructions. PCR reactions were performed as described previously [30,31]. The products were separated on a 2% agarose-1xTAE gel.…”

Werner Syndrome

“…Of these, 15 are localized within the coding region and 11 of these result in alterations in amino acid sequence [75, 76]. A limited association study of the two known WRN SNPs with relatively high heterogeneity suggested that WRN may be involved in determining longevity, possibly by modulating the risk of a variety of common age-related disorders, including atherosclerosis.…”

“…This might be explained by the presence of linkage disequilibrium between 1074 Leu/Phe and 1367 Cys/Arg in some populations [76, 77]. The relative contribution of WRN polymorphisms to the risk of age-related disorders or longevity may not be nearly as high as other major known genetic risk factors, for example, polymorphisms in ApoE [75]. However, these studies are beginning to provide hints that WRN may indeed be involved in the “normal” aging process in the general population.…”

The Werner’s syndrome 4330T>C (Cys1367Arg) gene variant does not affect the in vitro cytotoxicity of topoisomerase inhibitors and platinum compounds

“…Previous epidemiologic studies suggest that this SNP plays a protective role against a variety of age-related disorders including risk of atherosclerosis and its complications [3, 32]. It has been speculated that, due to the presence of another basic amino acid (Arg coded by the variant allele) in the nuclear localization signal motif, this variant might enhance the translocation of the protein into the nucleus, allowing for more efficient activity of the WS protein in response to various challenges [4]. Moreover, it has been reported that B-lymphoblastoid cell lines (LCLs) having at least one copy of the mutated allele are more resistant to the cytotoxic effect induced by 4NQO, a genotoxic agent [17].…”