Genotype and allele frequency compared between nonagenarians (N=250) and controls (N=400) for IL1RN, IL1B, IL1A, TNFA, IL10 and IL6

Nonagenarians (N=250) Controls (N=400) P n % n % IL1RN (VNTR) Genotype A1/A1 122 48.8 199 49.8 0.81 A1/A2 102 40.8 156 39.0 0.65 A1/A3 7 2.8 7 1.8 0.27 A2/A2 15 6.0 37 9.3 0.14 A2/A3 4 1.6 1 0.3 0.06 Allele frequency A1 71.0 70.0 0.86 A2 27.0 29.0 0.51 A3 2.0 1.0 0.08 IL1B−511 Genotype A1/A1 106 42.4 146 36.5 0.13 A1/A2 109 43.6 182 45.5 0.64 A2/A2 35 14.0 72 18.0 0.18 Allele frequency A1 64.0 59.0 0.08 A2 36.0 41.0 IL1B+3953 Genotype A1/A1 135 54.0 206 51.5 0.53 A1/A2 98 39.2 164 41.0 0.65 A2/A2 17 6.8 30 7.5 0.74 Allele frequency A1 74.0 72.0 0.53 A2 26.0 28.0 IL1A−889 Genotype A1/A1 121 48.4 167 41.7 0.10 A1/A2 106 42.4 201 50.3 0.05 A2/A2 23 9.2 32 8.0 0.59 Allele frequency A1 70.0 67.0 0.31 A2 30.0 33.0 TNFA−308 Genotype A1/A1 175 70.0 275 68.7 0.74 A1/A2 72 28.8 120 30.0 0.74 A2/A2 3 1.2 5 1.3 0.96 Allele frequency A1 84.0 84.0 0.76 A2 16.0 16.0

Nonagenarians (N=250) Controls (N=400) P n % n % IL10−1082 Genotype A/A 83 33.2 135 33.8 0.89 A/G 120 48.0 177 44.3 0.35 G/G 47 18.8 88 22.0 0.33 Allele frequency A 57.0 56.0 0.64 G 43.0 44.0 IL6−174 Genotype C/C 63 25.2 118 29.5 0.23 C/G 130 52.0 201 50.3 0.66 G/G 57 22.8 81 20.3 0.44 Allele frequency C 51.0 55.0 0.23 G 49.0 45.0

Statistical analysis: The prevalence of different genotypes, and frequencies of alleles, allele 2 carrier status of studied cytokine gene polymorphisms and carriage of haplotypes of IL-1 complex were compared between nonagenarians and the control group using Fischer’s exact test for 2×2 tables. Prevalences of each genotype and gene frequencies were compared between nonagenarians and controls using dichotomized variables (e.g. IL1RN genotype A1/a!: 122/250 vs. 199/400). All statistical analyses were conducted with STATISTICA software (StatSoft Inc., Tulsa, OK). The tests were conducted using Fischer’s exact test for 2×2 tables.

4. Discussion

There have been some reports of gene variants either being or not associated with longevity. This study is the first to attempt to search for the association between cytokine gene variants and longevity.

as hematopoiesis. The cytokines participating in the regulation of inflammatory response are functionally divided into pro-inflammatory (IL-1, IL-6, TNF) and anti-inflammatory (IL-1RA, IL-10) molecules. Polymorphisms of these cytokine genes have an effect on cytokine profile induced and thus may have an important role in the genetic regulation of inflammatory response and of resistance and susceptibility to infectious and autoimmune diseases.

Aging is associated with immune deterioration and dysregulation of cytokines, which are deeply involved in the pathogenesis of most age-related diseases. A number of independent studies have demonstrated that some cytokine gene poly- morphisms are associated with diabetic nephropathy (Blakemore et al., 1996; Loughrey et al., 1998), Alzheimer’s disease (Papassotiropoulos et al., 1999), single- vessel coronary heart disease (Francis et al., 1999) and autoimmune diseases (Cantagrel et al., 1999; Hajeer et al., 1998; Perrier et al., 1998).

Because the maintenance of optimal antimicrobial defence is a central survival factor in advanced age (Fagiolo et al., 1993; Franceschi et al., 1995), and because cytokine gene variants play a part in the dysregulation of cytokines and some age-related diseases, we therefore asked whether or not these cytokine gene poly- morphisms could account for one part of the genetic component of human longevity.

The data showed that no statistically significant differences were found between the nonagenarians and controls by comparing genotype distributions, allelic fre- quencies and allele 2 carrier status of studied cytokine gene polymorphisms. Furthermore, we asked whether or not these cytokine gene polymorphisms in combination, i.e. certain haplotypes could account for one part of the genetic component. Still there is no statistically significant difference in the first common haplotype carriage (IL1A−889 A1+, IL1B+3953 A1+, IL1B−511 A2+, IL1RN VNTR A2+) and the second haplotype carriage (IL1A−889 A2+, IL1B+3953 A2+, IL1B−511 A1+, IL1RN VNTR A1+) between nonagenari- ans and controls.

We selected a study population of Finnish nonagenarians who display less selection due to random environmental insults but still represent highly selected population enabling study of survival after 90 years of age (Jylha¨ and Hervonen, 1999) and controls who were 18–60 years old. Concerning the control group, some of them, in fact, will turn out to be nonagenarians in the future, however this kind of overlap between the two populations cannot be expected to be rather frequent. In reference to our studied nonagenarian group, they consisted of not only healthy individuals but also individuals with some age-related diseases. Although completed clinical data concerning this group is not available at this moment; we do know some of them suffering from one or more age-related diseases. It would be interesting to perform further analyses in this group to compare the genotype distributions, allelic frequencies and even certain haplotypes between the individuals with different kinds of age-related diseases and those without.

Longevity is a complex trait, which likely results from a lucky combination of genetic and non-genetic factors (De Benedictis, 1996; Pepe et al., 1998). It is possible that the plethora of environmental and life history related to stochastic factors exert stronger influence on the survival to 100+ than the genetic traits (Deiana et al., 1999). Studies attempting to assess the overall genetic influence on variations in the human life span indicated that no more than 20–25% of the variation in the adult life spans can be attributed to genetic variation among individuals (Yashin et al., 1999; Andersen-Ranberg et al., 1999).