,

–

Christiansen,L.,Bathum,L.,Andersen-Ranberg,K.,Jeune,B.,Christensen, K.,

Modest implication of interleukin-

promoter polymorphism in longevity. Mech. Aging Dev.

,

–

Colhoun, H.M., M

eigue, P.M., Smith, G.D.,

Problems of reporting genetic associations with complex outcomes. Lancet

,

–

Ershler, W.B., Keller, E.T.,

Age-associated increased interleukin-

gene exepression, late-life diseases, and frailty. Annu. Rev. Med.

,

–

Fishman, D., Faulds, G., Jeffery, R., Mohamed-Ali, V., Yudkin, J.S., Humpries, S., Woo, P.,

The effect of novel polymorphism in the interleukin-

(IL-

) gene on IL-

transcription and plasma IL-

levels, and an association with systemic-onset juvenile chronic arthritis. J. Clin. Invest.

,

–

Franceschi, C., Valensin, S., Bonafe, M., Paolisso, G., Yashin, A.I., Monti, D., De Benedictis, G.,

The network and remodeling theories of aging: historical background and new perspectives. Exp. Gerontol.

,

–

Freedman, M.L., Reich, D., Penney, K.L., M

onald, G.J., Mignault, A.A., Petterson, N., Gabriel, S.B., Topol, E.J., Smoller, J.W., Pato, C.N., Pato, M.T., Petryshen, T.L., Kolonel, L.N., Lander, E.S., Sklar, P., Henderson, B., Hirschhorn, J.N., Altshuler, D.,

Assessing the impact of population stratification on genetic association studies. Nat. Genet.

,

–

Marchini, J., Cardon, L.R., Phillips, M.S., Donnelly, P.,

The effect of human population structure on large genetic association studies. Nat. Genet.

,

–

Wang, X.Y., Hurme, M., Jylha¨, M., Hervonen, A.,

Lack of association between human longevity and polymorphisms of IL-

cluster, IL-

, IL-

and TNF-a genes in Finnish nonagenarians. Mech. Aging Dev.

,

–

References

by collecting the mortality data of the nonagenarians, representing mortality between 90 and 95 years of age. These data were analyzed in relation to the original IL-6 (cid:1)174G/C genotyping. In this follow-up setting, we could thus, avoid the possible problems associated with the quality of the control group(seeabove).ThedatashowninTable1.demonstratethat the genotype distribution was significantly different between the survivors (n = 114) and non-survivors (n = 171). The frequency of the G/G genotype was higher in the survivor group and consequently, the frequency of allele G was significantly higher than in the group of non-survivors. Thus, the presence of allele C (i.e. genotypes CC and CG) is a risk factor for mortality (relative risk of C-carriers 1.94, 95% confidence intervals 1.11–3.35, p = 0.019). The effect of IL-6 genotype on the survival time (after the age of 90) was also tested using the Kaplan–Meier analysis, which gave similar results (p = 0.04 log rank test).

Taken together, the present data confirm, without the possible bias introduced by genetic differences between the cases and controls, that the IL-6 gene is involved in the genetic regulation of longevity. The advantageous allele was (cid:1)174*G, thus being in accordance with the data of Christiansen et al. (2004). This effect was strong in females but could not be reliably analyzed separately in males