An interleukin-18 polymorphism is associated with reduced serum concentrations and better physical functioning in older people.
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.
Frayling
Timothy M
TM
Peninsula Medical School, Exeter, United Kingdom. tim.frayling@pms.ac.uk
Rafiq
Sajjad
S
Murray
Anna
A
Hurst
Alison J
AJ
Weedon
Michael N
MN
Henley
William
W
Bandinelli
Stefania
S
Corsi
Anna-Maria
AM
Ferrucci
Luigi
L
Guralnik
Jack M
JM
Wallace
Robert B
RB
Melzer
David
D
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
D015415:Biomarkers; D020382:Interleukin-18; D004247:DNA