Association Between a Functional Variant of the
            <i>KLOTHO</i>
            Gene and High-Density Lipoprotein Cholesterol, Blood Pressure, Stroke, and Longevity

Arking, Dan E.; Atzmon, Gil; Arking, Albert; Barzilai, Nir; Dietz, Harry C.

doi:10.1161/01.res.0000157171.04054.30

Cited by 271 publications

(238 citation statements)

References 28 publications

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“…This observation may be explained by the relatively small number of BRCA1 patients who harbored the VV genotype. Interestingly, a study of Ashkenazi Jews also showed differential effects of heterozygosity compared with homozygosity for the V allele (Arking et al, 2005). Thus, heterozygous individuals were at significantly lower risk for stroke, whereas homozygous individuals had significantly higher risk compared with wild-type individuals.…”

Section: Discussionmentioning

confidence: 99%

Functional variant of KLOTHO: a breast cancer risk modifier among BRCA1 mutation carriers of Ashkenazi origin

et al. 2009

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Klotho is a transmembrane protein that can be shed and act as a circulating hormone and is a putative tumor suppressor in breast cancer. A functional variant of KLOTHO (KL-VS) contains two amino acid substitutions F352V and C370S and shows reduced activity. Germ-line mutations in BRCA1 and BRCA2 substantially increase lifetime risk of breast and ovarian cancers. Yet, penetrance of deleterious BRCA1 and BRCA2 mutations is incomplete even among carriers of identical mutations. We examined the association between KL-VS and cancer risk among 1115 Ashkenazi Jewish women: 236 noncarriers, 631 BRCA1 (185delAG, 5382insC) carriers and 248 BRCA2 (6174delT) carriers. Among BRCA1 carriers, heterozygosity for the KL-VS allele was associated with increased breast and ovarian cancer risk (hazard ratio 1.40, 95% confidence intervals 1.08-1.83, P ¼ 0.01) and younger age at breast cancer diagnosis (median age 48 vs 43 P ¼ 0.04). KLOTHO and BRCA2 are located on 13q12, and we identified linkage disequilibrium between KL-VS and BRCA2 6174delT mutation. Studies in breast cancer cells showed reduced growth inhibitory activity and reduced secretion of klotho F352V compared with wildtype klotho. These data suggest KL-VS as a breast and ovarian cancer risk modifier among BRCA1 mutation carriers. If validated in additional cohorts, the presence of KL-VS may serve as a predictor of cancer risk among BRCA1 mutation carriers.

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Section: Discussionmentioning

confidence: 99%

Functional variant of KLOTHO: a breast cancer risk modifier among BRCA1 mutation carriers of Ashkenazi origin

et al. 2009

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“…A follow-up study on Ashkenazi-Jewish populations replicated the heterozygous advantage but not the homozygous disadvantage (Arking et al 2005) ( Table 2).…”

Section: Introductionmentioning

confidence: 87%

Lack of replication of genetic associations with human longevity

et al. 2007

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The exceptional longevity of centenarians is due in part to inherited genetic factors, as deduced from data that show that first degree relatives of centenarians live longer and have reduced overall mortality. In recent years, a number of groups have performed genetic association studies on long-living individuals (LLI) and young controls to identify alleles that are either positively or negatively selected in the centenarian population as consequence of a demographic pressure. Many of the reported studies have shown genetic loci associated with longevity. Of these, with the exception of APOE, none have been convincingly reproduced. We validated our populations by typing the APOE locus. In addition, we used 749 American Caucasian LLI, organized in two independent tiers and 355 American Caucasian controls in the attempt to replicate previously published findings. We tested Klotho (KL)-VS variant (rs952706), Cholesteryl Ester Transfer Protein (CETP) I405V (rs5882), Paraoxonase 1 (PON1) Q192R (rs662), Apolipoprotein C-III (APOC3) -641C/A (rs2542052), Microsomal Transfer Protein (MTP) -493G/T (rs2866164) and apolipoprotein E (APOE) e2 and e4 isoforms, (rs7412 and rs429358) haplotypes respectively. Our results show that, at present, except for APOE, none of the selected genes show association with longevity if carefully tested in a large cohort of LLI and their controls, pointing to the need of larger populations for case-control studies in extreme longevity.

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“…Changes in KL gene expression would, over time, impact normal function of all downstream pathways. Evidence of such an effect is observed in the KL polymorphism KL VS (Arking et al 2002) where slight changes in KL function increases risk of disease (Arking et al 2002(Arking et al , 2003(Arking et al , 2005Invidia et al 2010;Wolf et al 2010). Of course, the overall contribution of a small change in one gene would not induce a dramatic phenotype in humans as it does in the KL knockout mouse; however, small changes in KL and numerous other genes would add up over time.…”

Section: Many Small Changes Can Affect Gene Expressionmentioning

confidence: 99%

Promoter methylation and age-related downregulation of Klotho in rhesus monkey

King

Rosene

Abraham

2011

AGE

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While overall DNA methylation decreases with age, CpG-rich areas of the genome can become hypermethylated. Hypermethylation near transcription start sites typically decreases gene expression. Klotho (KL) is important in numerous age-associated pathways including insulin/IGF1 and Wnt signaling and naturally decreases with age in brain, heart, and liver across species. Brain tissues from young and old rhesus monkeys were used to determine whether epigenetic modification of the KL promoter underlies age-related decreases in mRNA and protein levels of KL. The KL promoter in genomic DNA from brain white matter did not show evidence of oxidation in vivo but did exhibit an increase in methylation with age. Further analysis identified individual CpG motifs across the region of interest with increased methylation in old animals. In vitro methyl modification of these individual cytosine residues confirmed that methylation of the promoter can decrease gene transcription. These results provide evidence that changes in KL gene expression with age may, at least in part, be the result of epigenetic changes to the 5′ regulatory region.

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Association Between a Functional Variant of the KLOTHO Gene and High-Density Lipoprotein Cholesterol, Blood Pressure, Stroke, and Longevity

Abstract: Abstract

Cited by 271 publications

References 28 publications

Functional variant of KLOTHO: a breast cancer risk modifier among BRCA1 mutation carriers of Ashkenazi origin

Functional variant of KLOTHO: a breast cancer risk modifier among BRCA1 mutation carriers of Ashkenazi origin

Lack of replication of genetic associations with human longevity

Promoter methylation and age-related downregulation of Klotho in rhesus monkey

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