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journal homepage: www.elsevier.com/locate/issn/10434666

of functional polymorphic variants of inflammation-related genes and CCR5 in long-lived individuals

Marina Laplana, Joan Fibla

Departament de Ciències Mèdiques Bàsiques, Unitat de Genètica Humana, IRBLleida, Universitat de Lleida, C/ Montserrat Roig, 2. 25008 Lleida, Spain

Article history: Received 4 October 2011 Received in revised form 23 December 2011 Accepted 24 December 2011 Available online 20 January 2012

Although persistent inflammation has been related to unsuccessful aging, a pro-inflammatory status is the common phenotype in older people. To assess for a genetic component in the inflammatory status of the oldest we studied the distribution of two polymorphic chemokine pathway genes, RANTES and CCR5, in elderly. RANTES (cid:2)403G/A and RANTES Int1.1T/C polymorphisms and CCR5D32 polymorphism were genotyped in 104 elderly and 110 controls. RANTES (cid:2)403A and RANTES Int1.1C alleles have been associated with pro-inflammatory and anti-inflammatory status, respectively. CCR5D32 abrogates func- tional receptor expression of the pro-inflammatory CCR5-mediated action. Prevalence of RANTES (cid:2)403G allele, associated in other studies with high RANTES production, was reduced in elderly males, compared with controls. In addition, RANTES pro-inflammatory haplotype (cid:2)403A-Int1.1T was overrepre- sented in elderly males, while RANTES anti-inflammatory haplotype (cid:2)403G-Int1.1C was overrepresented in elderly females. Our results suggest a sex-specific RANTES inflammatory genetic determinant that could contribute to the known sex-related differences in aging.

  2012 Elsevier Ltd. All rights reserved.

1. Introduction

in recruitment of leukocytes to the inflammation site. Natural CCR5 ligands are the C-C motif chemokine ligands CCL3, CCL4 and CCL5, which is also known as RANTES (regulated upon activa- tion normal T-cell expressed and secreted). Two polymorphisms have been described in the RANTES gene, a promoter polymor- phism ((cid:2)403G/A, rs2107538) whose (cid:2)403A allele increases the pro- moter transcriptional activity, which results in high serum RANTES levels favouring a pro-inflammatory status [4], and an intronic polymorphism (Int1.1T/C, rs2280789) whose Int1.1C variant has been associated with low RANTES expression and an anti-inflam- matory status [5]. A 32 bp insertion/deletion polymorphism has been described in exon 3 of the CCR5 gene (CCR5D32, rs333) that abrogates functional CCR5 receptor expression, weakening the pro-inflammatory CCR5-mediated action [6]. The CCR5D32 allele reaches appreciable frequencies only in Europe, following a latitu- dinal cline distribution that is higher in the north and lower in the south. Studies have demonstrated that the CCR5D32 allele is re- lated to reduction of portal inflammation during hepatitis C (HCV) infection, delayed progression in multiple sclerosis, protec- tion against cardiovascular diseases (acute myocardial infarction and severe coronary heart disease) and attenuation of the inflam- matory response that delays progression of atherosclerotic lesions

The immune system’s positive protective effect against patho- gens and the spread of tumor cells can also become a detrimental chronic inflammation affecting longevity. Studies on the genetic component of longevity have tended to evaluate the role of the im- mune system genes, especially those involved in inflammation. Re- sults obtained reveal that persistent activation of inflammatory status is related to unsuccessful aging and that avoiding a persis- tent inflammation contributes to healthy aging. However, a pro- inflammatory status is the common phenotype in older people [1].

Inflammatory response could be affected by changes in chemo- kine gene transcription and receptor expression levels due to poly- morphisms at the corresponding genes. Previous studies of chemokine factors related to age-related disease and longevity re- vealed attrition or change in frequency of chemokine alleles with ageing [2,3]. Chemokines are small chemotactic cytokines (C-C) with a pivotal role in leukocyte trafficking and activation. Their biological effects are exerted via interaction with G protein-cou- pled receptors that mediate intracellular signals. C-C chemokine receptor type 5 (CCR5) is the co-receptor for macrophages and dual (T cell and macrophage) tropic immunodeficiency viruses and is involved in the migration of monocytes, NK cells and Th1 cells toward an increasing concentration of b-chemokines, which results

To assess the possibility of a genetic component of inflamma- tory status in the elderly, we studied the distribution of functional polymorphic variants of two genes from the chemokine inflamma- tory pathway, RANTES and CCR5, in long-lived individuals.

2. Methods

According to the inflammation-linked effect attributed to both RANTES (cid:2)403G/A and Int1.1T/C polymorphisms, we can presume an anti-inflammatory effect for the (cid:2)403G-Int1.1C (GC) haplotype and the opposite pro-inflammatory effect for the (cid:2)403A-Int1.1T (AT) haplotype. Haplotype-specific test showed that anti-inflam- matory GC haplotype was overrepresented in the elderly cohort (P = 0.04), mainly due to the overrepresentation in females (Peto OR = 8.3; 95%CI = 2–34; P = 0.005). In contrast, pro-inflammatory AT haplotype was overrepresented in elderly males (OR = 4.9; 95%CI = 0.97–24.7; P = 0.03).