Polymorphisms at the Werner locus: II. 1074Leu/Phe, 1367Cys/Arg, longevity, and atherosclerosis

Castro, E.; Edland, Steven D.; Lei, Lin; Ogburn, Charles E.; Deeb, Samir S.; Brown, Gregory P.; Panduro, Arturo; Riestra, Roberto; Tilvis, Reijo S.; Louhija, Jukka; Penttinen, Risto; Erkkola, Risto; Wang, Lan; Martin, George M.; Oshima, Junko

doi:10.1002/1096-8628(20001211)95:4<374::aid-ajmg14>3.3.co;2-w

Cited by 21 publications

(29 citation statements)

References 25 publications

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“…Investigating WRN polymorphism and haplotype frequencies in different ethnic groups certainly strengthens the power of association and predisposition studies on agerelated morbidities since distinct populations exhibit different and specific gene frequencies (4,36).…”

Section: Discussionmentioning

confidence: 89%

“…In a Finnish population, the R allele frequency did not differ between newborns and centenarians, indicating the absence of a protective age-related effect of this allele. The allele frequencies also did not differ among North American adults, Mexican newborns and Finnish newborns and centenarians (3,4).…”

Section: Discussionmentioning

confidence: 93%

“…WS patients develop the appearance of advanced aging in middle-age, including age-related disorders usually seen in normal elderly subjects, such as atherosclerosis, diabetes mellitus, osteoporosis, and neoplasias. The major cause of death is myocardial infarction (1)(2)(3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

“…Specific WRN polymorphisms have been studied to understand the impact of molecular variants on longevity in WS as well as other age-related disorders and can yield new insights to its biological and pathological role (3,4,8,11). The identification of genetic polymorphisms as risk factors for complex diseases in elderly people can be relevant for their prevention, diagnosis and prognosis.…”

Section: Introductionmentioning

confidence: 99%

“…Population studies of WRN 1074 Leu/ Phe and 1367 Cys/Arg polymorphisms in Finnish, Mexican and North American subjects revealed only a tendency for the 1074 Phe allele to be associated with coronary stenosis and that the 1367 Arg/Arg (RR) genotype tended to protect against coronary artery occlusion, although without statistical significance (4).…”

Section: Introductionmentioning

confidence: 99%

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

Smith

Silva

Araújo

et al. 2005

Braz J Med Biol Res

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Werner syndrome (WS) is a premature aging disease caused by a mutation in the WRN gene. The gene was identified in 1996 and its product acts as a DNA helicase and exonuclease. Some specific WRN polymorphic variants were associated with increased risk for cardiovascular diseases. The identification of genetic polymorphisms as risk factors for complex diseases affecting older people can improve their prevention, diagnosis and prognosis. We investigated WRN codon 1367 polymorphism in 383 residents in a district of the city of São Paulo, who were enrolled in an Elderly Brazilian Longitudinal Study. Their mean age was 79.70 ± 5.32 years, ranging from 67 to 97. This population was composed of 262 females (68.4%) and 121 males (31.6%) of European (89.2%), Japanese (3.3%), Middle Eastern (1.81%), and mixed and/or other origins (5.7%). There are no studies concerning this polymorphism in Brazilian population. These subjects were evaluated clinically every two years. The major health problems and morbidities affecting this cohort were cardiovascular diseases (21.7%), hypertension (83.7%), diabetes (63.3%), obesity (41.23%), dementia (8.0%), depression (20.0%), and neoplasia (10.8%). Their prevalence is similar to some urban elderly Brazilian samples. DNA was isolated from blood cells, amplified by PCR and digested with PmaCI. Allele frequencies were 0.788 for the cysteine and 0.211 for the arginine. Genotype distributions were within that expected for the Hardy-Weinberg equilibrium. Female gender was associated with hypertension and obesity. Logistic regression analysis did not detect significant association between the polymorphism and morbidity. These findings confirm those from Europeans and differ from Japanese population.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Smith

Silva

Araújo

et al. 2005

Braz J Med Biol Res

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Ethnic‐specific WRN mutations in South Asian Werner syndrome patients: potential founder effect in patients with Indian or Pakistani ancestry

Saha

Lessel

Nampoothiri

et al. 2013

Molec Gen & Gen Med

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Werner syndrome is a rare autosomal recessive disorder characterized by multiple features consistent with accelerated aging. It is caused by mutations in the WRN gene, which encodes a RecQ type helicase. To date, more than 70 disease-causing mutations have been reported. While founder mutations and a corresponding relatively high incidence of WS have been reported in Japan and Sardinia, such mutations have not been previously described among patients of South Asian descent. Here we report two novel WRN mutations in three pedigrees. A homozygous c.561A>G mutation in exon 6 was identified both in a pedigree from Kerala, India and in a British patient of Pakistani ancestry. Although c.561A>G does not alter the corresponding amino acid (p.K187K), it creates a cryptic splice site resulting in a 98bp deletion at the mRNA level (r.557-654del98) followed by a frameshift (p.K187fs). These two cases shared the same haplotype across the WRN gene, and were distinct from another Indian Werner patient with a homozygous stop codon mutation, c.2855 C>A (p.S952*) in exon 24. As the Indian population increases and the awareness of Werner syndrome grows, we anticipate that more cases will be identified with these founder mutations among South Asian Werner syndrome patients.

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From old organisms to new molecules: integrative biology and therapeutic targets in accelerated human ageing

Cox

Faragher

2007

Cell. Mol. Life Sci.

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Abstract. Understanding the basic biology of human ageing is a key milestone in attempting to ameliorate the deleterious consequences of old age. This is an urgent research priority given the global demographic shift towards an ageing population. Although some molecular pathways that have been proposed to contribute to ageing have been discovered using classical biochemistry and genetics, the complex, polygenic and stochastic nature of ageing is such that the process as a whole is not immediately amenable to biochemical analysis. Thus, attempts have been made to elucidate the causes of monogenic progeroid disorders that recapitulate some, if not all, features of normal ageing in the hope that this may contribute to our understanding of normal human ageing. Two canonical progeroid disorders are Werners syndrome and Hutchinson-Gilford progeroid syndrome (also known as progeria). Because such disorders are essentially phenocopies of ageing, rather than ageing itself, advances made in understanding their pathogenesis must always be contextualised within theories proposed to help explain how the normal process operates. One such possible ageing mechanism is described by the cell senescence hypothesis of ageing. Here, we discuss this hypothesis and demonstrate that it provides a plausible explanation for many of the ageing phenotypes seen in Werners syndrome and Hutchinson-Gilford progeriod syndrome. The recent exciting advances made in potential therapies for these two syndromes are also reviewed.

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Polymorphisms at the Werner locus: II. 1074Leu/Phe, 1367Cys/Arg, longevity, and atherosclerosis

Cited by 21 publications

References 25 publications

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

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

Ethnic‐specific WRN mutations in South Asian Werner syndrome patients: potential founder effect in patients with Indian or Pakistani ancestry

From old organisms to new molecules: integrative biology and therapeutic targets in accelerated human ageing

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