Mechanisms of Ageing and Development 126 (2005) 417–418

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(cid:1)174G/C polymorphism and longevity: a follow-up study

M. Hurmea,* , T. Lehtima¨kib , M. Jylha¨c , P.J. Karhunend , A. Hervonenc

Abstract

Increased rate of inflammation has been observed to be associated with aging. This is manifested, e.g. as increased blood levels of proinflammatory cytokines, such as interleukin-6 (IL-6). The production of IL-6 is, at least partially, genetically determined the single nucleotide polymorphism (SNP) at the promoter ((cid:1)174G/C) being decisive. Consequently, some studies have demonstrated that the (cid:1)174G/C genotype frequencies are different in very old persons as compared to younger ones. However, the results published this far have been conflicting. One of the main confounding factors in these kind of case/control association studies is the undetected difference in the population structure. To avoid this, we now have collected the mortality data of our cohort of 285 nonagenarians (representing mortality between 90 and 95 years of age) and correlated these to the IL-6 genotype. The frequency of (cid:1)174 allele G was clearly higher in the survivors (n = 114) than in the non-survivors (n = 171). # 2004 Elsevier Ireland Ltd. All rights reserved.

Keywords: Longevity; Cytokine; Gene polymorphism

entirely reliable (Freedman et al., 2004). One obvious way to avoid the effects of population stratification is to follow the emergence of a given disease, or more generally, of a given phenotypic change, in a population cohort genotyped at a certain time point. Naturally, this method is not applicable very often.

Case/control association studies are presently very often used to examine the effect of a given ‘‘candidate’’ gene in a disease. The reproducibility of these studies is, however, not very good (for a review, see Colhoun et al., 2003). Probably, one of the main reasons to this is the presence of undetected population structure, i.e. the cases and controls could be derived from subpopulations differing in regard of the prevalence of the disease or in the frequency of the genotypes of the studied candidate gene (Marchini et al., 2004). In some studies the effect of the population structure has been controlled by analyzing simultaneously several unlinked genetic markers, but even this method is not

There is increasing evidence suggesting that the rate of inflammation is inversely correlated to longevity, i.e. elevated levels of various inflammatory molecules, such as tumor necrosis factor-a and IL-6, seem to lead to increased mortality at older age (reviewed in Ershler and Keller, 2000; Franceschi et al., 2000; Bruunsgaard et al., 2001). Production of these cytokines is, at least partially, genetically determined, and consequently, it is possible that these genes are partly responsible for the observed genetic

0047-6374/$ – see front matter # 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.mad.2004.10.001

Table 1

because of their low number (67 at the age of 90, of whom 20 survived to the age of 95). Moreover, as our follow-up study started at the age of 90, it can be concluded that IL-6 exerts its effect after this age. Bonafe et al. (2001) observed in their cohort collected from Italy that the GG genotype was disadvantageous for longevity but only in men. These discrepant data could naturally be due to the population stratification, as discussed above. However, it is interesting to note that the genotype distribution of IL-6 (cid:1)174G/C, even in the control population, was significantly different form that in Finland and Denmark, the GG genotype being much more frequent. The possible effects of these kinds of ethnic differences on the results of genetic studies of longevity remain to be established.

IL-6 (cid:1)174G/C genotypes and allele frequencies of persons surviving (n = 114) or not surviving (n = 171) from 90 to 95 years of age

Genotype (n, %) p (chi2-test) CC CG GG Survivors 24 (21.1) 55 (48.3) 35 (30.7) Non-survivors 50 (29.2) 89 (52.1) 32 (18.7) 0.046 Allele frequency p (chi2-test) Allele C Allele G Survivors 45.2 54.8 Non-survivors 55.3 44.7 0.018

component of longevity. In the case of the IL-6 gene, the single nucleotide polymorphisms (SNP) in the promoter are associated with the rate of transcription and the G/C base exchange at the position (cid:1)174 seems to be decisive (Fishman et al., 1998). The association studies using this SNP as the marker have been disturbingly incoherent, without an obvious reason. For example, in case/control studies of longevity (i.e. in comparing the genotype frequency of very old persons to that of younger controls) strikingly conflicting results have been reported. Bonafe et al. (2001) observed that the IL-6 (cid:1)174 G/G genotype was disadvantageous for longevity, while Christiansen et al. (2004) found just the opposite, i.e. its frequency was increased in their cohort of very old persons. Moreover, in our cohort of nonagenarians we did not observe any difference in the genotype or allele frequency when compared to a cohort of 400 healthy blood donors (mean age 40 years) (Wang et al., 2001).

Acknowledgements

This work was supported by grants from The Research Foundation of Tampere University Hospital, The Tampere Tuberculosis Foundation and Emil Aaltonen Foundation.

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