Mechanisms of Ageing and Development 126 (2005) 417-418 www.elsevier.com/locate/mechagedev

174G/C Polymorphism and Longevity: A Follow-Up Study

M. Hurmea*, T. Lehtimakib, M. Jylhac, P.J. Karhunend, A. Hervonenc

Abstract 

Increased rates of inflammation have been observed to be associated with aging, which is manifested by increased blood levels of proinflammatory cytokines like interleukin-6 (IL-6). The production of IL-6 is, at least partially, genetically determined by the single nucleotide polymorphism (SNP) at the promoter (174G/C), which is decisive. Some studies have demonstrated that the 174G/C genotype frequencies are different in very old persons as compared to younger ones. However, the results published thus far have been conflicting. One of the main confounding factors in these kinds of case/control association studies is the undetected difference in population structure. To avoid this, we 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 174 allele G was clearly higher in the survivors (n=114) than in the non-survivors (n=171). 

Keywords: Longevity; Cytokine; Gene polymorphism

There is increasing evidence suggesting that the rate of inflammation is inversely correlated to longevity; 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; consequently, it is possible that these genes are partly responsible for the observed genetic 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 position 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. 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-6 174 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). 

Because of their low number (67 at the age of 90, of whom 20 survived to the age of 95), we could not analyze the data separately for men and women. Furthermore, 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 population stratification, as discussed above. However, it is interesting to note that the genotype distribution of IL-6 174G/C, even in the control population, was significantly different from that in Finland and Denmark, with 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 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 

In this follow-up setting, we could avoid possible problems associated with the quality of the control group by collecting the mortality data of the non