The main conclusion to be drawn from the part of the study dealing with haplotypes versus single genotypes is that all four polymorphisms exhibit allelic association to such − an extent that investigation of the 174G/C polymorphism only is sufficiently informative.

In a sub-sample of the subjects included we thus found − − that the 174G/C and the 597G/A polymorphisms are in almost complete linkage disequilibrium, in accordance with results presented previously by others (Georges et al., 2001; Brull et al., 2001). Furthermore, our results confirm the − nearly constant association of the 373(A) (T) allele with 8 12 − the 174C allele previously reported by others, although in considerably smaller samples (Villuendas et al., 2002; Terry − et al., 2000). The 572C allele was found to be associated − with the 174G allele at all times. It has previously been − suggested that presence of the 572C allele modulates the − effect of the 174G allele on IL6 expression (Brull et al., − 2001). However, the frequency of the rare 572C allele did not change with age in the subjects included in this study − and the increase seen for the 174GG homozygotes with − − age was evident in both 572G and 572C allele carriers. Our results thus indicate that the effect of this allele is of minor importance, at least in the Danish population.

− Overall, we find that the proportion of 174GG homozy- gotes increases modestly with age, indicating a weak protec- tive effect of this genotype. However, this increase is mainly followed by a concomitant decrease in GC heterozygotes rather than in CC homozygotes, as may be expected if the C allele is associated with decreased survival chance.

Establishment of the entire promoter haplotype reveals − that the frequency of the 174C allele only decreases with − − age when this is inherited together with 572G/ 373(A) 8 (T) . In their work on the functional effect of the four IL-6 12 promoter polymorphisms using reporter gene expression studies Terry et al. (2000) demonstrated that expression of

In summary, investigation of IL-6 promoter polymor- phisms in this very large group of 47–100 years old subjects indicates that a possible solitary role for IL-6 promoter variations in ageing and disease predisposition is probably fairly small although the modest increase in the frequency

L. Christiansen et al./Mechanisms of Ageing and Development 125 (2004) 391–395

of 174GG homozygotes with age indicates a weak pro- tective effect of this genotype.

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