Mendelian Randomization Using rs5744256

IL-18 serum concentrations (in the InCHIANTI data only) and walking time due to the rs5744256 SNP, thus excluding reverse causation and confounding. Using instrumental variables analyses (Table 4), we found that there was a significant association between IL-18 serum concentra- tions and walk time due to the three rs5744256 genotypes (linear regression coefficient¼ 0.324; 95% CI, 0.050–0.598; p ¼ .021). This is analogous to showing that the observed association between rs5744256 and functioning is consistent with the expected effect given the association between the SNP and IL-18 concentrations and the association between IL-18 concentrations and functioning. The estimate of the regression coefficient between IL-18 concentrations and walking speed using genotypes was larger than the observed regression coefficient (0.082; 95% CI, 0.029–0.135; p value for difference ¼ .048). This difference may be due to chance or could reflect possible regression dilution bias caused by the error in the measurement of IL-18 concentrations.

Associations between serum markers and disease or functioning in observational studies always need to be viewed cautiously, as confounding and reverse causation are difficult to control in conventional analyses. Genetic variation is randomly inherited and is fixed at conception, and when such variation alters risk factor levels, these properties can be exploited to reduce confounding and reverse causation. The instrumental variable model pre- sented has been used before for this purpose (14). In our study, the model clearly shows an un-confounded associ- ation of IL-18 concentrations with walk time when using IL- 18 SNPs. If confirmed, this association indicates that IL-18 may play an active role in age-related physical decline.

D ISCUSSION

In this study, we have tested three hypotheses on the relationships between IL-18 concentrations, IL-18 gene tagging SNPs, and functioning in younger old age. We have shown positive associations between higher IL-18 serum concentrations and tested physical functioning. We showed that the minor, C, allele of the rs5744256 SNP in IL-18 is

The SNP associated with both IL-18 levels and altered functioning in old age is in intron 3 of the IL-18 gene and

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