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promoter: a possible role of polymorphisms in expression regulation. J Neuroimmunol.

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gene variants detected from functional but not association study. Biochem Biophys Res Commun.

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has no obvious function. Based on HapMapII data in Caucasians, the association could be due to nine other SNPs, including several outside of the IL-18 gene. It is likely that one or more of these SNPs alters IL-18 gene expression, and direct measurement of expression is needed. Previous in vitro experiments have shown IL-18 gene expression to be altered by two promoter polymorphisms, (cid:3)607 (rs1946518) and (cid:3)137 (rs187238) (28,29). The data from HapMap indicates that we have captured the (cid:3)607 SNP with an r2 of 0.56 using rs1293344. This SNP was not associated with IL- 18 levels (p ¼ .11), and (cid:3)607 is not in strong linkage disequilibrium (LD) with the SNP we found is most strongly associated with levels (correlation, r2 ¼ 0.14 with rs5744256). The (cid:3)137 SNP is not in HapMap, and we have not analyzed it further. It therefore remains possible that there is further variation in the IL-18 gene that alters serum levels of IL-18.

Conclusion

There is mounting evidence that inflammation is a core process contributing to aging. IL-18 is a potent proinflam- matory cytokine and is a good candidate for contributing to inflammation-mediated aging. We have analyzed common variation in the IL-18 gene, and found that a common allele is strongly correlated with IL-18 concentration and, through this, with altered physical functioning in early old age. If replicated, these results indicate that associations between IL-18 and physical functioning are unlikely to be due to con- founding or reverse causation. IL-18 may be an active factor and not a by-product in age-related decline in physical functioning.

ACKNOWLEDGMENTS

This work was supported in part by National Institutes of Health/National Institute on Aging (NIH/NIA) Grant R01 AG24233-01, and by the Intramural Research Program, NIA, NIH. D. M. is supported by a National Health Service Executive National Public Health Career Scientist Award (Ref: PHCSA/00/002). The InCHIANTI study was supported as a ‘‘targeted project’’ (ICS 110.1\RS97.71) by the Italian Ministry of Health, by the National Institute on Aging (N01-AG-916413, N01-AG-821336, 263 MD 9164 13, and 263 MD 821336).

Address correspondence to Timothy M. Frayling, Peninsula Medical School, Magdalen Rd., Exeter, EX1 2LU, U.K. E-mail: tim.frayling@pms. ac.uk

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