Frequency of Werner helicase 1367 polymorphism and age-related morbidity in an elderly Brazilian population

Smith, Marı́lia de Arruda Cardoso; Silva, M.d.a.; Araújo, Lara Miguel Quirino; Ramos, Luiz Roberto; Lábio, Roger Willian de; Burbano, Rommel Rodrı́guez; Peres, C.; Andreoli, Sérgio Baxter; Payão, Spencer Luíz Marques; Cendoroglo, Maysa Seabra

doi:10.1590/s0100-879x2005000700008

Cited by 13 publications

(10 citation statements)

References 34 publications

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“…WS patients develop the appear-162 ance of advanced ageing in middle age, including agerelated disorders usually seen in the normal elderly, such as atherosclerosis, myocardial infarction, diabetes mellitus, osteoporosis and neoplasias [23][24][25][26][27][28]. A lack of association of WRN codon 1367 polymorphism with myocardial infarction in a Brazilian cohort study, carried out by our group, confirmed findings observed in samples with similar allele frequencies and differed significantly from findings obtained for Japanese samples [29].…”

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confidence: 71%

Polymorphisms of the TP53 codon 72 and WRN codon 1367 in individuals from Northern Brazil with gastric adenocarcinoma

et al. 2005

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Gastric cancer is the second most frequent type of neoplasia and also the second most common cause of death in the world. TP53 codon 72, which produces variant proteins with an arginine (Arg) or proline (Pro), has been reported to be associated with cancers of the lung, oesophagus, stomach and cervix. Werner's syndrome (WS) is a premature ageing disease caused by a mutation in the WRN gene. The WRN protein acts as a DNA helicase and as an exonuclease. WRN codon 1367 produces variant proteins with an Arg or cysteine (Cys). This polymorphism has been studied, in order to understand the clinical impact of the molecular variants in WS and in age-related disorders. In the present study, the TP53 codon 72 and the WRN codon 1367 polymorphisms were investigated in 54 gastric adenocarcinoma patients (31 diffuse-type and 25 intestinal-type) and 54 controls. DNA samples were extracted, and PCR-RFLP was utilised for genotyping TP53 codon 72 and WRN codon 1367. The allele frequencies of the TP53 polymorphism were: Arg=0.74 and Pro=0.26. The allele frequencies of the WRN polymorphism were: Cys=0.73 and Arg=0.27. The crude genotypic frequencies in gastric cancer patients were similar to those of the controls, but in the WRN codon 1367 polymorphisms the mean age tended to be higher in the Arg/Arg genotypes. There also was an association, although not statistically significant, between the presence of Helicobacter pylori and the genotypes Cys/Cys and Cys/Arg and a higher percentage of cardia cancer among the Arg/Arg genotypes, and of non-cardia cancer among genotypes Cys/Cys and Cys/Arg. These findings may be a reflection of differences in the interaction between WRN codon 1367 polymorphisms and local factors in the stomach. To our knowledge, this is the first study to examine a genetic polymorphism of the WRN gene in cancer. The precise mechanisms of action of the TP53 and WRN polymorphisms involved in the aetiopathogeny of this disease need further investigation.

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confidence: 71%

Polymorphisms of the TP53 codon 72 and WRN codon 1367 in individuals from Northern Brazil with gastric adenocarcinoma

et al. 2005

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“…Previous epidemiological studies have reported association of others diseases, but not ARC, with WRN rs1346044, which is a non-synonymous variation that causes a conversion of Cys to Arg at amino acid position 1367 (Bohr et al 2004;Hirai et al 2005;Payao et al 2004;Smith et al 2005;Ye et al 1997;Castro et al 2000Castro et al , 1999Kuningas et al 2006;Morita et al 1999;Ogata et al 2001). The association of WRN rs1346044 with myocardial infarction was first reported in a Japanese population (Ye et al 1997).…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms of the WRN gene and DNA damage of peripheral lymphocytes in age-related cataract in a Han Chinese population

Jiang

Zhou

et al. 2013

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Werner syndrome is caused by mutations in the DNA repair Werner helicase (WRN) gene and characterized by accelerated aging including cataracts. Age-related cataract (ARC) cases (N = 504) and controls (N = 244) were recruited from a population-based study to evaluate the association of single-nucleotide polymorphisms (SNPs) of WRN and another DNA repair gene (human 8-oxoguanine DNA N-glycosylase 1) with ARC. Among the five SNPs tested, only WRN rs1346044 was found to be significantly associated between cases and controls before multiple-testing adjustment. The minor C allele of rs1346044 was associated with ARC with an odds ratio (OR) of 0.66, suggesting a protective role of the C allele for developing ARC. The stratification analysis on the subtypes of ARC showed that rs1346044 was significantly associated with cortical cataract, but not with nuclear, posterior subcapsular, and mixed types after multiple-testing adjustment (OR = 0.51, p< 0.01). The genetic model analysis showed that the results fit the dominant model (OR = 0.44, p < 0.001). The comet assay used to assess the extent of DNA damage in peripheral lymphocytes of ARC cases found that the DNA damage in lymphocytes from patients with CC genotype was significantly less than that in patients with TT genotype. We concluded that the C allele of rs1346044, a non-synonymous SNP resulting in the conversion of Cys to Arg at amino acid position 1367 of WRN, alters susceptibility to ARC, especially the cortical type of the disease, in the Han Chinese. The underlying mechanism of its protective role might be related to the improved DNA repair function.

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“…A polymorphic WRN C1367R variant residing near the nuclear localization signal was reported to be associated with protection against myocardial infarction [241,242]; however, the C1367R polymorphism had no effect on enzyme function [243,244] or localization [243] and did not influence coronary heart disease for individuals drawn from the Baltimore Longitudinal Study of Aging [243] or Leiden 85-plus Study [245]. Other studies have also begun to investigate the correlations between WRN polymorphisms and age-related illness [246][247][248]. Most recently, a significant association of the WRN C1367R variant allele C with the tumour suppressor p53 gene in familial breast cancer was reported [249].…”

Section: Recq Polymorphismsmentioning

confidence: 99%

Mechanisms of RecQ helicases in pathways of DNA metabolism and maintenance of genomic stability

Sharma

Doherty

Brosh

2006

Biochemical Journal

237

264

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Helicases are molecular motor proteins that couple the hydrolysis of NTP to nucleic acid unwinding. The growing number of DNA helicases implicated in human disease suggests that their vital specialized roles in cellular pathways are important for the maintenance of genome stability. In particular, mutations in genes of the RecQ family of DNA helicases result in chromosomal instability diseases of premature aging and/or cancer predisposition. We will discuss the mechanisms of RecQ helicases in pathways of DNA metabolism. A review of RecQ helicases from bacteria to human reveals their importance in genomic stability by their participation with other proteins to resolve DNA replication and recombination intermediates. In the light of their known catalytic activities and protein interactions, proposed models for RecQ function will be summarized with an emphasis on how this distinct class of enzymes functions in chromosomal stability maintenance and prevention of human disease and cancer.Key words: aging, cancer, DNA repair, genomic instability, helicase, RecQ. INTRODUCTIONUnderstanding the molecular mechanisms of RecQ helicases is fundamental to deciphering the roles of these enzymes in cellular DNA metabolism. Since the discovery of Escherichia coli RecQ and its implicated role in genetic recombination, the world of RecQ helicases has become significantly more complex with the identification and characterization of a number of eukaryotic RecQ helicases that are important in the replicational stress response and maintenance of genomic stability.Classification of RecQ helicases and molecular-genetic analyses of their biochemical and cellular functions gained prominence with the understanding that certain rare genetic disorders [WS (Werner syndrome), BS (Bloom syndrome) and RTS (Rothmund-Thomson syndrome)] are a consequence of mutations in the human RecQ genes WRN, BLM and RECQ4 respectively. WS is characterized by premature aging with an elevated risk of age-associated diseases such as cancer, atherosclerotic cardiovascular disease, diabetes mellitus (Type II) and osteoporosis [1]. Epigenetic inactivation of WRN is detected in a number of human cancers [2]. BS is associated with a very high incidence of different types of cancers, both solid tumours and leukaemia, and also manifested by skin disorders, proportional dwarfism, immunodeficiency and male sterility [1]. People with RTS, also known as poikiloderma congenitale, displays growth deficiency, photosensitivity with poikilodermatous skin changes, early greying and hair loss, juvenile cataracts and a predisposition to malignancy, especially osteogenic sarcomas [1]. Apart from RTS, RECQ4 mutations were detected in Finnish patients with an autosomal recessive disorder RAPADILINO syndrome [radial hypoplasia/aplasia, patellae hypoplasia/aplasia and cleft or highly arched palate, diarrhoea and dislocated joints, little size (height at least 2 S.D. smaller than the average height) and limb malformation, nose slender and normal intelligence] [3]. Although many features o...

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Frequency of Werner helicase 1367 polymorphism and age-related morbidity in an elderly Brazilian population

Cited by 13 publications

References 34 publications

Polymorphisms of the TP53 codon 72 and WRN codon 1367 in individuals from Northern Brazil with gastric adenocarcinoma

Polymorphisms of the TP53 codon 72 and WRN codon 1367 in individuals from Northern Brazil with gastric adenocarcinoma

Polymorphisms of the WRN gene and DNA damage of peripheral lymphocytes in age-related cataract in a Han Chinese population

Mechanisms of RecQ helicases in pathways of DNA metabolism and maintenance of genomic stability

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