gene C/G 174 polymorphism in nonagenarian and octogenarian subjects in the BELFAST study. Reciprocal effects on IL-6, soluble IL-6 receptor, and IL-10 in serum and monocytes. 

Irene M. Rea, Owen A. Ross*, Marilyn Armstrong, Susan McNerlan, Denis H. Alexander, Martin D. Curran, Derek Middleton

a Department of Geriatric Medicine, Queens University of Belfast, Whitla Medical Building, 97 Lisburn Road, Belfast, UK
b Northern Ireland Histocompatibility and Immunogenetics Centre, Belfast City Hospital, Belfast BT9 7TS, UK
c Immunology and Microbiology Department, Royal Trust Group, Queens University of Belfast, Belfast, UK
d Received 1 July 2002; received in revised form 3 October 2002; accepted 20 December 2002

Abstract:

In this study, we assessed any change in the frequency of the GG homozygotes of the 174 IL-6 polymorphism with increasing age. We argued that if IL-6 tracks with functional disability and age-related diseases, there may be attrition or reduction in the frequency of homozygous subjects who produce higher levels of IL-6 in serum in older survivors in a population. We tested this hypothesis in a large group of free-living, mentally competent nonagenarian and octogenarian subjects from the Belfast Elderly Longitudinal Ageing Study (BELFAST study) and found that the frequency of GG homozygotes with IL-6-174C/G polymorphism decreases with age by about 10%, compared with young controls. In addition, we found that CC homozygotes have higher serum levels of IL-6 levels compared with GG (P<0.055), with reciprocal and significant changes in the anti-inflammatory IL-10 (P<0.05). Both IL-6 and IL-10 were spontaneously produced from separated mononuclear cell monolayers in elderly subjects, with significantly higher levels of secreted IL-10 supernatant levels (P<0.05) at 20 h for G allele subjects carrying the IL-6-174C/G polymorphism. In conclusion, in the BELFAST study, there appears to be a reduction in the frequency of GG homozygotes in the octo/nonagenarian age group and a higher serum IL-6 level associated with CC homozygotes with reciprocal changes for the anti-inflammatory cytokine IL-10.

Keywords: Interleukin-6-gene; Nonagenarian and octogenarian subjects; BELFAST study

Introduction:

IL-6, an important cytokine at the center of the immune response, is increased in serum in elderly people. Although the cause is unknown, it has been associated with functional disability, cognitive decline, and stroke in older people. Elevation of IL-6, an acute phase reactant, is also increased in a range of age-related disorders such as autoimmune disease (OShea et al., 2002), atherosclerosis (van der Meer et al., 2002), congestive cardiac failure (Wollert and Drexler, 2001), hypertension (Humphries et al., 2001), as well as in acute infection (Suffredini et al., 1999). 

Recently a promoter C/G 174 polymorphism of IL-6 has been identified which has functional activity with some groups reporting an increase in serum IL-6 associated with GG homozygotes compared with CC homozygotes (Fishman et al., 1998). However, lately other groups have found an increase associated with CC homozygosity (Brull et al., 2001, 2002; Olivieri et al., 2002; Jones et al., 2001; Kiplinen et al., 2001). The dichotomy of results in relation to IL-6-174C/G polymorphism and IL-6 levels remains unresolved with a few studies. 

In this study, we assessed any change in the frequency of the GG homozygotes of the 174 IL-6 polymorphism with increasing age. We argued that if IL-6 tracks with functional disability and age-related diseases, there may be attrition or reduction in the frequency of homozygous subjects who produce higher levels of IL-6 in serum in older survivors in a population. We tested this hypothesis in a large group of free-living, mentally competent nonagenarian and octogenarian subjects from the Belfast Elderly Longitudinal Ageing Study (BELFAST study) and found that the frequency of GG homozygotes with IL-6-174C/G polymorphism decreases with age by about 10%, compared with young controls. 

In addition, we found that CC homozygotes have higher serum levels of IL-6Spontaneous secretion into the supernatants was increased 100-fold in G allele subjects at 20 h, with a significant increase for GG compared with CC subjects (P<0.055) (Figure 2).

In this study, several main findings were noted. First, it was observed that there was a trend for a reduced frequency of the GG polymorphism of IL-6 in the octo/nonagenarians from the BELFAST study group compared with younger subjects in the local population, aged 20-45 years of age. This trend appeared more marked in elderly males compared with females (Ross et al., 2003), but both groups showed an almost 10% decrease. The effect of IL-6-174C/G genotype on IL-6 and IL-10 secretion into supernatants from in vitro monocyte monocultures is shown in Figure 2. Although the spontaneous secretion of IL-6 into the supernatants increased, there was a significant decrease in GG homozygotes and C allele carriers for IL-10 secretion at 20 h.

A finding which deserves further focused attention and priority study is that there are well-described differences in ApoE genotype frequency across Europe and world populations which undoubtedly link into pathological and environmental disease mechanisms and differential morbidity and mortality rates from atherosclerotic-related disease, and there may be similar effects for C/G IL-6 genotypes.