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, 2 3 4,5 6 Henley, Stefania Bandinelli, Anna-Maria Corsi, Luigi Ferrucci, Jack M. Guralnik, 8 1 Robert B. Wallace, and David Melzer

and Department of Medical and Surgical Critical Care, University of Florence, Italy. Studies Section, Clinical Research Branch, Gerontology Research Center, National Institute on Aging, Baltimore, Maryland. 7Laboratory of Epidemiology, Demography and Biometry, National Institute on Aging, Bethesda, Maryland. 8Department 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- EstablishedPopulationsforEpidemiologicalStudyoftheElderly(EPESE).Wetestedthreecommonpolymorphismsagainst 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 ¼ .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; p¼.00016) in age sex adjusted logistic regression models. There was no association with Activities of Daily Living (p ¼ .26) or Mini-Mental State Examination score (p ¼ .66). The C allele of the IL-18 polymorphism rs5744256 reduced serum concentrations of IL-18 by 39 pmol/mL per allele (p¼.00001). The rs5744256 single nucleotide polymorphism was also associated with shorter walk times in InCHIANTI (n¼662, p¼.016) and Iowa- EPESE (n¼995, p¼.026). In pooled ranked models rs5744256 was also associated with higher SPPB scores (n¼1671, p ¼ .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 ¼ .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 in age-related functional impairment, but these findings need independent replication.

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 random- ized 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 proinflamma- tory 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 inflamma- tion is a key driver of aging (9–11), IL-18 is a good candidate for causing early onset of disability in older people.

IL-18 serum concentrations increase with age (12), and are higher in healthy centenarians compared to younger controls (13). However, an association of higher IL-18 serum concentrations with aging phenotypes may not be causal. IL-18 concentrations may be raised as a by-product of disease or other processes producing physical decline. It

The role of common variation in the IL-18 gene in aging- related disease and disability has not been well studied.

Table 1. Details of Participants Aged 65–80 Years in the InCHIANTI and Iowa-EPESE Studies

ulation, to add further evidence on the role of IL-18 in aging related phenotypes.

Trait InCHIANTI Iowa-EPESE N 674 997 % Male 46% 37% Age, y 72 75 ADL (n poor functioning   1 ADL; 24 (3.4%) 444 (43%) InCHIANTI-requiring help, Iowa-EPESE difficulty with ADL) Summary Physical Performance Battery (range 0–12) Mean (SD) 10.61 (2.4) 8.50 (2.6) N poor functioning 115 (17%) 203 (20%) Walking times, s 7-m walk 8-ft walk Mean (SD) 6.26 (2.4) 3.94 (1.8) N poor functioning 131 (20%) 193 (19%) Cognitive function (MMSE in InCHIANTI, SPMSQ in Iowa-EPESE) Mean (SD) 25.7 (3.2) 0.6 (0.9) N poor functioning ((cid:2) 23 MMSE, 141 (20%) 119 (12%)   2 SPMSQ)

M ETHODS

The InCHIANTI Study

InCHIANTI (21) is a study of decline of mobility in late life, with a sample representative of the population aged 65 or older of two small towns in Tuscany, Italy. The par- ticipants were all of white European origin. The Italian National Institute of Research and Care of Aging Insti- tutional Review Board ratified the study protocol.