,

–

Leineweber, K., Buscher, R., Bruck, H., Brodde, O.E.,

Beta-adrenoceptor poly- morphisms. Naunyn Schmiedebergs Arch. Pharmacol.

,

–

Levy, D., D

alma, S.R., Benjamin, E.J., O’Donnell, C.J., Parise, H., Hirschhorn, J.N., Vasan, R.S., Izumo, S.,Larson, M.G.,

Phenotype-genotype association grid: a convenient method for summarizing multiple association analyses. BMC Genet.

,

Matheson, M.C., Ellis, J.A., Raven, J., Johns, D.P., Walters, E.H., Abramson, M.J.,

Beta

-adrenergic receptor polymorphisms are associated with asthma and COPD in adults. J. Hum. Genet.

,

–

M

arthy, M.I., Abecasis, G.R., Cardon, L.R., Goldstein, D.B., Little, J., Ioannidis, J.P., Hirschhorn, J.N.,

Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nat. Rev. Genet.

,

–

Medawar, P.B.,

An Unsolved Problem of Biology; An Inaugural Lecture Delivered at University College, London,

December,

H.K. Lewis and Co., London. Melzer, D., Hurst, A.J., Frayling, T.,

Genetic variation and human aging: progress and prospects. J. Gerontol. A: Biol. Sci. Med. Sci.

,

–

Murabito, J.M., Evans, J.C., Nieto, K., Larson, M.G., Levy, D., Wilson, P.W.,

Prevalence and clinical correlates of peripheral arterial disease in the Framing- ham Offspring Study. Am. Heart J.

,

–

Olshansky, S.J., Perry, D., Miller, R.A., Butler, R.N.,

Pursuing the longevity dividend: scientific goals for an aging world. Ann. N. Y. Acad. Sci.

,

–

Peel, N., Bartlett, H., M

lure, R.,

Healthy ageing: how is it defined and measured? Aust. J. Ageing

,

–

Penke, L., Maniega, S.M., Houlihan, L.M., Murray, C., Gow, A.J., Clayden, J.D., Bastin, M.E., Wardlaw, J.M., Deary, I.J.,

White Matter Integrity in the Splenium of the Corpus Callosum is Related to Successful Cognitive Aging and Partly Mediates the Protective Effect of an Ancestral Polymorphism in ADRB

Behav. Genet.. Petrone,A.,Zavarella,S.,Iacobellis,G.,Zampetti,S.,Vania,A.,D

ietro,S.,Galgani,A., Leonetti, F., Di Mario, U., Buzzetti, R.,

Association of beta

adrenergic

Major limitation of our study is a small sample of the oldest-old individuals that prevents generalization of the case of antagonistic pleiotropy to the very old ages. Given concerns on definitive validity of strategy on replication of genetic associations in different setting (see above), the best strategy would be to replicate the results on antagonistic pleiotropy in the same cohort but followed for longer time period. This is a reasonable strategy given the ongoing nature of the FHS.

Acknowledgements

The research reported in this paper was supported by the National Institute on Aging (NIA) grants R01 AG-028259, R01-AG- 027019, and R01-AG-030612. The data were provided by Boston University and the National Heart, Lung, and Blood Institute (NHLBI) under data and material distribution agreement for NIA grant R01AG030612. The Framingham Heart Study (FHS) is conducted and supported by the NHLBI in collaboration with Boston University (Contract No. N01-HC-25195). This manuscript was notprepared in collaborationwith investigatorsof the FHS and does not necessarily reflect the opinions or views of the Framingham Heart Study, Boston University, or NHLBI.

References

References Bao, X., Mills, P.J., Rana, B.K., Dimsdale, J.E., Schork, N.J., Smith, D.W., Rao, F., Milic, M., O’Connor, D.T., Ziegler, M.G.,

Interactive effects of common beta

- adrenoceptor haplotypes and age on susceptibility to hypertension and recep- tor function. Hypertension

,

–

Barrett,J.C.,Fry,B.,Maller,J.,Daly,M.J.,

Haploview:analysisandvisualization of LD and haplotype maps. Bioinformatics

,

–

Barzilai, N., Atzmon, G., Schechter, C., Schaefer, E.J., Cupples, A.L., Lipton, R., Cheng, S.,Shuldiner,A.R.,

Uniquelipoproteinphenotypeandgenotypeassociated with exceptional longevity. JAMA

,

–

Benovic, J.L.,

Novel beta

-adrenergic receptor signaling pathways. J. Allergy Clin. Immunol.

, S

–S

Bochdanovits, Z., Gosso, F.M., van den Berg, L., Rizzu, P., Polderman, T.J., Pardo, L.M., Houlihan, L.M., Luciano, M., Starr, J.M., Harris, S.E., Deary, I.J., de Geus, E.J., Boomsma, D.I., Heutink, P., Posthuma, D.,

A functional polymorphism under positive evolutionary selection in ADRB

is associated with human intelligence with opposite effects in the young and the elderly. Behav. Genet.

,

–

Bracken, A.P., Pasini, D., Capra, M., Prosperini, E., Colli, E., Helin, K.,

EZH

is downstream of the

B-E

F pathway, essential for proliferation and amplified in cancer. EMBO J.

,

–

Brodde, O.E.,

a. Beta

- and beta

-adrenoceptor polymorphisms and cardio- vascular diseases. Fundam. Clin. Pharmacol.

,

–

Brodde, O.E.,

b. Beta-

and beta-

adrenoceptor polymorphisms: functional importance, impact on cardiovascular diseases and drug responses. Pharmacol. Ther.

,

–

Brodde,O.E.,Michel,M.C.,

Adrenergicandmuscarinicreceptorsinthehuman heart. Pharmacol. Rev.

,

–

Buscher, R., Herrmann, V., Ring, K.M., Kailasam, M.T., O’Connor, D.T., Parmer, R.J., Insel, P.A.,

Variability in phenylephrine response and essential hyperten- sion: a search for human alpha(

B)-adrenergic receptor polymorphisms. J. Pharmacol. Exp. Ther.

,

–

Christensen,K.,Johnson,T.E.,Vaupel,J.W.,

Thequestforgeneticdeterminants of human longevity: challenges and insights. Nat. Rev. Genet.

,

–

Contopoulos-Ioannidis, D.G., Manoli, E.N., Ioannidis, J.P.,

Meta-analysis of the association of beta

-adrenergic receptor polymorphisms with asthma pheno- types. J. Allergy Clin. Immunol.

,

–

Cupples, L.A., Arruda, H.T., Benjamin, E.J., D’Agostino Sr., R.B., Demissie, S., D