An Interleukin-18 Polymorphism is Associated with Reduced Serum Concentrations and Better Physical Functioning in Older People. Timothy M. Frayling, Sajjad Rafiq, Anna Murray, Alison J. Hurst, Michael N. Weedon, Henley, Stefania Bandinelli, Anna-Maria Corsi, Luigi Ferrucci, Jack M. Guralnik, Robert B. Wallace, and David Melzer from the Department of Medical and Surgical Critical Care at the University of Florence, Italy; Studies Section at the Clinical Research Branch of the Gerontology Research Center at the National Institute on Aging in Baltimore, Maryland; and Laboratory of Epidemiology, Demography and Biometry at the National Institute on Aging in Bethesda, Maryland; and Department of Epidemiology at the University of Iowa in Iowa City.

Background: The proinflammatory cytokine interleukin-18 (IL-18) is associated with major disabling conditions, although whether as a 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 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. It is also possible that unaccounted for confounding factors may result in misleading associations. Assuming an ethnically homogeneous population, genes are randomly assigned to offspring at conception. Reverse causation or confounding factors are therefore very unlikely to affect polymorphisms. A gene variant that alters a potential risk factor provides a natural experiment analogous to a randomized controlled trial of the risk factor: If a polymorphism changes a risk factor but does not produce a linked and proportionate change in outcomes, then by implication the risk factor is unlikely to play an active role in producing the outcomes. This Mendelian randomization approach has recently shown that the association between C-reactive protein and features of the metabolic syndrome is unlikely to be causal (14).

(IL-18) is a powerful proinflammatory cytokine, with effects on both innate and acquired immunity (1). Raised serum concentrations of IL-18 have been implicated in atherosclerosis (2), myocardial infarction (3), rheumatoid arthritis (4), inflammatory bowel disease (5), asthma (6), and response to infection (7). IL-18 is also a possible mediator of neurodegeneration (8). As many of these conditions contribute to disability, and inflammation is a key driver of aging (9,11), IL-18 is a good candidate for causing early onset of disability in older people.