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An Interleukin-18 Polymorphism Is Associated With Reduced Serum Concentrations and Better Physical Functioning in Older People

¹ Peninsula Medical School, Exeter, United Kingdom.
² Department of Statistics, University of Plymouth, United Kingdom.
³ Laboratory of Clinical Epidemiology, Italian National Research Council on Aging, Geriatrics Department, Florence, Italy.
⁴ Tuscany Regional Health Agency, Florence, Italy.
⁵ I.O.T. and Department of Medical and Surgical Critical Care, University of Florence, Italy.
⁶ Longitudinal Studies Section, Clinical Research Branch, Gerontology Research Center, National Institute on Aging, Baltimore, Maryland.
⁷ Laboratory of Epidemiology, Demography and Biometry, National Institute on Aging, Bethesda, Maryland.
⁸ Department of Epidemiology, University of Iowa, Iowa City.

Background. The proinflammatory cytokine interleukin-18 (IL-18) is associated with major disabling conditions, although whether as byproduct or driver is unclear. The role of common variation in the IL-18 gene on serum concentrations and functioning in old age is unknown.

Methods. We used 1671 participants aged 65–80 years from two studies: the InCHIANTI study and wave 6 of the Iowa-Established Populations for Epidemiological Study of the Elderly (EPESE). We tested three common polymorphisms against IL-18 concentration and measures of functioning.

Results. In the InCHIANTI study, a 1 standard deviation increase in serum IL-18 concentrations was associated with an increased chance of being in the 20% of slowest walkers (odds ratio 1.45; 95% confidence interval, 1.17–1.80; p =.0007) and 20% of those with poorest function based on the Short Physical Performance Battery Score (odds ratio 1.52; 95% confidence interval, 1.22–1.89; p =.00016) in age sex adjusted logistic regression models. There was no association with Activities of Daily Living (p =.26) or Mini-Mental State Examination score (p =.66). The C allele of the IL-18 polymorphism rs5744256 reduced serum concentrations of IL-18 by 39 pmol/mL per allele (p =.00001). The rs5744256 single nucleotide polymorphism was also associated with shorter walk times in InCHIANTI (n = 662, p =.016) and Iowa-EPESE (n = 995, p =.026). In pooled ranked models rs5744256 was also associated with higher SPPB scores (n = 1671, p =.019). Instead of adjusting for confounders in the IL-18 walk time association, we used rs5744256 in a Mendelian randomization analysis: The association remained in instrumental variable models (p =.021).

Conclusion. IL-18 concentrations are associated with physical function in 65- to 80-year-olds. A polymorphism in the IL-18 gene alters IL-18 concentrations and is associated with an improvement in walk speed. IL-18 may play an active role in age-related functional impairment, but these findings need independent replication.

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