;

:

–

Saito Y, Yamagishi T, Nakamura T, Ohyama Y, Aizawa H, Suga T, Matsumura Y, Masuda H, Kurabayashi M, Kuro-o M, Nabeshima Y, Nagai R. Klotho protein protects against endothelial dysfunction. Biochem Biophys Res Commun.

;

:

–

Fukino K, Suzuki T, Saito Y, Shindo T, Amaki T, Kurabayashi M, Nagai R. Regulation of angiogenesis by the aging suppressor gene klotho. Biochem Biophys Res Commun.

;

:

–

Arking DE, Krebsova A, Macek M Sr, Macek M Jr, Arking A, Mian IS, Fried L, Hamosh A, Dey S, M

ntosh I, Dietz HC. Association of human aging with a functional variant of klotho. Proc Natl Acad Sci U S A.

;

:

–

Arking DE, Becker DM, Yanek LR, Fallin D, Judge DP, Moy TF, Becker LC, Dietz HC. KLOTHO allele status and the risk of early-onset occult coronary artery disease. Am J Hum Genet.

;

:

–

Tohyama O, Imura A, Iwano A, Freund JN, Henrissat B, Fujimori T, Nabeshima Y. Klotho is a novel beta-glucuronidase capable of hydro- lyzing steroid beta-glucuronides. J Biol Chem.

;

:

–

Xiao NM, Zhang YM, Zheng Q, Gu J. Klotho is a serum factor related to human aging. Chin Med J (Engl).

;

:

–

Takeshita K, Fujimori T, Kurotaki Y, Honjo H, Tsujikawa H, Yasui K, Lee JK, Kamiya K, Kitaichi K, Yamamoto K, Ito M, Kondo T, Iino S, Inden Y, Hirai M, Murohara T, Kodama I, Nabeshima Y. Sinoatrial node dysfunction and early unexpected death of mice with a defect of klotho gene expression. Circulation.

;

:

–

Yoshida T, Fujimori T, Nabeshima Y. Mediation of unusually high concentrations of

,

-dihydroxyvitamin D in homozygous klotho mutant mice by increased expression of renal

alpha-hydroxylase gene. Endo- crinology.

;

:

–

Yang J, Matsukawa N, Rakugi H, Imai M, Kida I, Nagai M, Ohta J, Fukuo K, Nabeshima Y, Ogihara T. Upregulation of

MP is a new functional signal pathway of Klotho in endothelial cells. Biochem Biophys Res Commun.

;

:

–

Takeshita K, Yamamoto K, Ito M, Kondo T, Matsushita T, Hirai M, Kojima T, Nishimura M, Nabeshima Y, Loskutoff DJ, Saito H, Murohara T. Increased expression of plasminogen activator inhibitor-

with fibrin

The consistent observation of opposing effects of one copy of the KL-VS allele versus carrying two copies offers a possible explanation for the relatively high frequency of the KL-VS allele in the general population (frequency 0.16). This model of “balancing selection” has been observed for the hemoglobin S allele in sickle cell anemia25 and for the  F508 allele in cystic fibrosis26 but has not been reported previously for a complex disease.

Study Limitations

Although the effect of the KL-VS allele on longevity for ;=7 individuals 79 years of age is validated in two independent populations through cross-sectional studies, and further evi- dence is provided through prospective studies, the opposite effect of the KL-VS allele on younger individuals is only statistically significant in one population (in part, because of absence of data for Czechs 4<7 75 years of age). Thus, a model in which there is a change in the effect of heterozygosity for the KL-VS allele on survival from negative to positive as age increases, although intriguing, remains to be validated through further studies. Particularly useful would be the ability to look at mortality data spanning a wide age range (65 to 95 years) that includes cause of death. This would allow for the testing of the hypothesis that the KL-VS allele may increase risk of mortality from one cause, such as cancer, while lowering risk for another, such as CVD. Another caveat is that the number of stroke events in the study was relatively few (30), and although the results are statistically significant because of the large effect, additional studies in cohorts with a greater number of events is necessary to determine more

Control C

Deaths, percent of total deaths, and death rates for the

leading cause of death in selected age groups, by race and sex: United States,

Natl Vital Stat Rep.

;

Peacock JM, Arnett DK, Atwood LD, Myers RH, Coon H, Rich SS, Province MA, Heiss G. Genome scan for quantitative trait loci linked to high-density lipoprotein cholesterol: the NHLBI Family Heart Study. Arterioscler Thromb Vasc Biol.

;

:

–

Mitani H, Ishizaka N, Aizawa T, Ohno M, Usui S, Suzuki T, Amaki T, Mori I, Nakamura Y, Sato M, Nangaku M, Hirata Y, Nagai R. In vivo klotho gene transfer ameliorates angiotensin II-induced renal damage. Hypertension.

;

:

–

Hamdi HK, Castellon R. A genetic variant of ACE increases cell survival: a new paradigm for biology and disease. Biochem Biophys Res Commun.

;

:

–

Lawes CM, Bennett DA, Feigin VL, Rodgers A. Blood pressure and stroke: an overview of published reviews. Stroke.

;

:

Hoekstra T, Geleijnse JM, Kluft C, Giltay EJ, Kok FJ, Schouten EG.

G/

G genotype of PAI-

gene is associated with reduced risk of stroke in elderly. Stroke.

;

:

–

Roth EF Jr, Friedman M, Ueda Y, Tellez I, Trager W, Nagel RL. Sickling rates of human AS red cells infected in vitro with Plasmodium falciparum malaria. Science.

;

:

–

Schroeder SA, Gaughan DM, Swift M. Protection against bronchial asthma by CFTR delta F

mutation: a heterozygote advantage in cystic fibrosis. Nat Med.

;

:

–

deposition in a murine model of aging, “Klotho” mouse. Semin Thromb Hemostasis.

;

:

–

Crisan D, Carr J. Angiotensin I-converting enzyme: genotype and disease associations. J Mol Diagn.

;

:

–

Margaglione M, Cappucci G, Colaizzo D, Giuliani N, Vecchione G, Grandone E, Pennelli O, Di Minno G. The PAI-

gene locus

G/

G polymorphism is associated with a family history of coronary artery disease. Arterioscler Thromb Vasc Biol.

;

:

–

Macek M Jr, Macek M Sr, Krebsova A, Nash E, Hamosh A, Reis A, Varon-Mateeva R, Schmidtke J, Maestri NE, Sperling K, Krawczak M, Cutting GR. Possible association of the allele status of the CS.

/Hh

polymorphism

(cid:

) of the CFTR gene with postnatal female survival. Hum Genet.

;

:

–