The association of RANTES polymorphisms with longevity has not yet been described. Our results denote a sex-specific association with functional RANTES polymorphisms. Pro-inflammatory RANTES alleles/haplotypes were positively associated with elderly males. In contrast, anti-inflammatory RANTES alleles/haplotypes showed a positive association with elderly females. Elevation of circulating levels of RANTES has been described in unstable angina pectoris patients as predictive of future cardiovascular adverse events [9]. Furthermore, a significant elevation of major C-C chemokines, including RANTES, has been described during the course of acute myocardial infarction that actively contributes to the pathophysiology of the disease. Finally, association studies of functional RANTES polymorphisms have been performed highlighting the role of RANTES in age-related diseases [4].

Genotype distribution differences between the elderly and controls showed statistical significance for Int1.1T/C polymorphism (P = 0.03), but not for CCR5D32 or 403G/A polymorphisms (Table 1). Sex-based differences between cohorts for the CCR5D32 polymorphism were not significant. Nevertheless, differences between elderly and control males were observed for the 403G/A genotype (P = 0.029) and allele distribution (OR = 3.2; 95%CI = 1.28-5; P = 0.012) (Table 1). In addition, differences were observed when 403A allele was modeled as dominant (OR = 4; 95%CI = 1.41-11.8; P = 0.01). We also found a genotype association for Int1.1C allele under recessive model (Peto OR = 8.8; 95%CI = 1.74-4.7; P = 0.008) that was mainly contributed by differences between elderly and control females (Peto OR = 8.4; 95%CI = 1.44-9.9; P = 0.02).

Our findings on RANTES allele/haplotype distribution among the elderly suggest a RANTES genetic determinant that is prone to a pro-inflammatory phenotype in males and an anti-inflammatory phenotype in females, which could contribute to the known sex-specific differences in aging. Sexual dimorphism in immune responsiveness has been reported with respect to genetic background. Some evidence of an increase in frequency of the IL-10 anti-inflammatory cytokine gene in long-lived males has been reported [12], and early work suggested that sexual dimorphism existed in immune responsiveness in the HLA supratype A1B8Cw7DR3 [13]. 

Haplotypes for RANTES gene markers were inferred by pLink software (pLink web resource available at http://pngu.mgh.harvard.edu/~purcell/plink/). Haplotype distribution between the elderly and controls in all subjects, males, and females showed significant differences (Omnibus test P = 0.02, P = 0.05 and P = 0.04, respectively) (Table 1). 

It has been previously described that the inflammation index, calculated as the sum of positive indicators such as C-reactive protein, plasma fibrinogen, and urinary albumin, shows sex differences and varies with age [14]. Women have a higher inflammation index during all life stages compared with men but slower rates of increase in inflammation with age. This can contribute to the decrease in the inflammation differences between the sexes in the elderly population (>80 years old) [14]. Moreover, it has been suggested that the female sex hormone estrogen may increase the expression of antioxidantFinding. Supplementary data associated with this article can be found in the online version at doi:10.1016/j.cyto.2011.12.021.