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Archives of Gerontology and Geriatrics

journal homepage: www.elsevier.com/locate/archger

Distributions of interleukin-6 (IL-6) promoter and metallothionein 2A (MT2A) core promoter region gene polymorphisms and their associations with aging in Turkish population

Zeliha Kayaaltı a,*, Levent S¸ahiner b, M. Emre Durakog˘lugil b, Tu¨ lin So¨ylemezog˘lu a

aAnkara University Institute of Forensic Sciences, Mamak Street, No:10, 06590, Dikimevi, Ankara, Turkey bAnkara Oncology Education and Research Hospital, Vatan Street, 06200, Yenimahalle, Ankara, Turkey

A B S T R A C T

Aging is determined as the product of an interaction among genetic, environmental and lifestyle factors. As interleukin-6 (IL-6) and metallothioneins (MTs) are related to inflammation and oxidative stress response, their genes are appropriate candidate for aging, age related diseases and infections. The aim of this study was to investigate the association between the IL-6 (cid:2)174 G/C promoter region and MT2A (cid:2)5 A/G core promoter region single nucleotide polymorphisms (SNPs) with longevityin Turkish population. Blood samples were collected from 354 individuals between 18 and 95 years of age. Individuals were classified into four groups according to their ages as 20–40, 41–60, 61–80, >80. IL-6 and MT2A polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymor- phism (PCR-RFLP) method. Mean ages of individuals with IL-6 (cid:2)74 C(cid:2) carriers and C+ carriers were 49.82   20.45 years and 59.82   16.82 years, respectively. For the MT2A polymorphism, mean ages were estimated as56.18 3 + 1 19.50years forG(cid:2)carriers and 47.59 y+ 1 13.45 years forG+carriers. Asaresult, whenthe IL-6 and MT2A polymorphisms were compared with the mean ages and age groups, statistically significant associations werefound(p < 0.001andp < 0.05,respectively).Inconclusion,thesedatasupportthattheIL-6 (cid:2)174 C+ carriers and MT2A (cid:2)5 G(cid:2) carriers may be more advantageous for longevity.

1. Introduction

polymorphisms(SNPs)havebeenidentified(TheNationalCenterfor Biotechnology Information; http://www.ncbi.nlm.nih.gov/SNP/). IL-6 gene polymorphisms affect the rate of synthesis or degradation ofIL-6.One ofthese polymorphismsin the IL-6 geneisthe (cid:2)174 G/C promoter region SNP and a significant association between (cid:2)174 G/ C polymorphism and some age-related diseases and longevity has been shown (Caruso et al., 2004; Van Bodegom et al., 2007).

Aging is determined as a complex interaction of genetic, epigenetic, and environmental factors, but a strong genetic component appears to have an impact on survival to extreme ages (Perls and Terry, 2003). Longevity is likely to be influenced by thousands of genes (Franceschi et al., 2000) and twin studies have indicated that approximately 20–30% of the overall variation in lifespan can be attributed to genetic factors (Hjelmborg et al., 2006). Inflammation and dysregulated production of inflammatory cytokines have an important role in the process of aging, as they affect an individual’s capacity to counteract noxious events such as pathogen infection, neurodegenerative disorders, autoimmunity and cancer (Caruso et al., 2004; Van Bodegom et al., 2007). An acute inflammatory response is beneficial for survival, but a chronic inflammatory state contributes to age-associated diseases. A reliable marker of inflammation is interleukin-6 (IL-6), the circulating level of which is increased in chronic diseases and aging (Jylha¨ et al., 2007). The IL-6 gene is highly polymorphic

IL-6 gene, which is located on chromosome 7p21, is expressed in lymphocytes, fibroblasts, macrophages in response to different types of inflammatory stimuli (Berghe et al., 2000). IL-6 also controls induction and expression of metallothioneins (MTs) which maintain homeostasis of zinc and copper (Mazzatti et al., 2008). During stress and inflammation, the gene expression of MT is induced by pro-inflammatory cytokines (IL-1, IL-6) (Davis and Cousins, 2000), which are also abnormally increased in the elderly (Sansoni et al., 2008) and high MT levels may be deleterious in aging. On the other hand, some MT polymorphisms and intracellular zinc ion bioavailability is fundamental in reducing inflammation and in recovering innate and adaptive immune response with subsequent achievement of healthy aging and longevity (Mocchegiani et al., 2009). A number of studies suggest that the major intracellular zinc-binding proteins, MTs, play an

* Corresponding author. Tel.: +90 312 319 2734; fax: +90 312 319 2077. E-mail address: kayaalti@medicine.ankara.edu.tr (Z. Kayaaltı).

0167-4943/$ – see front matter ©: 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.archger.2011.01.001

important regulatory role in zinc uptake, distribution, storage, and release (Giacconi et al., 2005).

 

MTs, which are low-molecular-weight, cysteine-rich, metal- binding proteins, are encoded by a family of genes located on chromosome 16q13 and MTs have 10 functional isoforms (Miles et al., 2000). In the basal level, MT2A is the most expressed MT isoform in the cell. The expression difference between the MT2A and other isoforms is attributed to the enhancer activity in MT2A. The richness in this activity greatly increases the MT2A expression in response to various inducers such as metals (Kita et al., 2006), interleukins(Cousins and Leinart, 1988), interferon (Sciavolino and Vilcek, 1995), tumor necrosis factor alpha (Ebadi et al., 1996) and glucocorticoid hormones (Samson and Gedamu, 1998).