title: An interleukin-18 polymorphism is associated with reduced serum concentrations and better physical functioning in older people.
abstract: 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Peninsula Medical School, Exeter, United Kingdom. tim.frayling@pms.ac.uk
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Frayling
authors.forename: Sajjad
authors.initials: S
authors.lastname: Rafiq
authors.forename: Anna
authors.initials: A
authors.lastname: Murray
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Hurst
authors.forename: Michael N
authors.initials: MN
authors.lastname: Weedon
authors.forename: William
authors.initials: W
authors.lastname: Henley
authors.forename: Stefania
authors.initials: S
authors.lastname: Bandinelli
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Corsi
authors.forename: Luigi
authors.initials: L
authors.lastname: Ferrucci
authors.forename: Jack M
authors.initials: JM
authors.lastname: Guralnik
authors.forename: Robert B
authors.initials: RB
authors.lastname: Wallace
authors.forename: David
authors.initials: D
authors.lastname: Melzer
mesh_terms: D000203:Activities of Daily Living; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000097:blood* / Q000235:genetics*; D000483:Alleles; D015415:Biomarkers / Q000097:blood; D004247:DNA / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D020382:Interleukin-18 / Q000097:blood / Q000235:genetics*; D007558:Italy; D008297:Male; D009043:Motor Activity / Q000502:physiology*; D021141:Nucleic Acid Amplification Techniques; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D014505:Urban Population
chemical_list: D015415:Biomarkers; D020382:Interleukin-18; D004247:DNA