A Genetic-Demographic Approach Reveals Male-Specific Association Between Survival and Tumor Necrosis Factor (A/G)-308 Polymorphism

Abstract

The (A/G)-308 polymorphism of the tumor necrosis factor alpha gene (TNF) is associated with age-related diseases, but its influence on longevity is controversial. We genotyped for this polymorphism 747 Italian volunteers (401 women and 346 men, age 19-110 years). By applying a genetic-demographic (GD) approach we found that, in men, the survival function of allele A carriers is lower than that of noncarriers at all the ages (p =.044). After defining (by exploiting again demographic information) three age classes, we found that the frequency of men carrying the A allele decreases with age (p =.019), thus confirming the GD analysis results. The same analyses gave negative results in women. Therefore, allele A has a detrimental effect on life expectancy, and this effect is specific to men. A haplotype analysis carried out in men by screening the TNFa, TNFc, and TNFe microsatellite polymorphisms (spanning about 20 kb) confirmed the association of the TNF region with life expectancy.

The frequency of Klotho KL-VS polymorphism in a large Italian population, from young subjects to centenarians, suggests the presence of specific time windows for its effect

“…These classes have been previously introduced on the basis of a synthetic survival curve constructed using historic mortality data taken from the Italian population from year 1890 onward (Passarino et al 2006;Cardelli et al 2008). In each age class and in each gender, the observed genotype frequencies were in agreement with those expected at Hardy-Weinberg equilibrium (P [ 0.05).…”

“…To determine whether KL-VS allele status influences human longevity, we analyzed a sample of Italian subjects divided into gender-specific age classes according to demographic information obtained from the survival function S(x) for the Italian population of the XX century (Passarino et al 2006;Cardelli et al 2008). In brief, the limit between the youngest class and the intermediate class has been chosen as the age at which the curvature of the survival function S(x) is negative and has the largest absolute value (formally, the age corresponding to the minimum value of the second derivative S 00 (x) of the survival function).…”

Cytokine Gene Polymorphisms and Alzheimer's Disease in Brazil

“…For genetic analyses of 10 important inflammatory mediators [ IL1-α , IL1-β , IL6 , IL8 , IL10 , IL12-β , IL18 , transforming growth factor ( TGF )-β 1 , toll-like receptor ( TLR )-4, and TNF ], one polymorphic site in each was selected based on prior evidence of a functional role for the mediator's expression [25,26,27,28,29,30,31,32,33]. Characteristics of selected markers are shown in table 1.…”

Immunosenescence and Immunogenetics of Human Longevity

“…Similarly, a recent study indicates that the genotype at the TNF(A/G)-308 locus affects the probability to reach extreme old age in a gender-specific manner. In particular, in men, the presence of allele A seems unfavorable to attain longevity [188] . The TNF(A/ G)-308 polymorphism, and in particular the A allele, has been associated with major age-related diseases, such as asthma, obesity, rheumatoid arthritis, systemic lupus erythematosus and insulin resistance [189][190][191][192][193][194] .…”