Journal
CYTOKINE
Volume 65, Issue 1, Pages 10-16Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.cyto.2013.10.002
Keywords
Chronic inflammation; Genome-wide association studies; Older adults
Funding
- Johns Hopkins Older Americans Independence Center [P30 AG021334]
- National Heart, Lung, and Blood Institute (NHLBI) [HL080295]
- National Institute on Aging (NIA) [AG-023629, AG-15928, AG-20098, AG-027058]
- Italian Ministry of Health [ICS110.1/RF97.71]
- U.S. National Institute on Aging [263 MD 9164, 263 MD 821336]
- [R01 AG027236]
- [R01 HL071862]
- [HHSN268201200036C]
- [N01-HC-85239]
- [N01-HC-85079]
- [N01-HC-85080]
- [N01-HC-85081]
- [N01-HC-85082]
- [N01-HC-85083]
- [N01-HC-85084]
- [N01-HC-85085]
- [N01-HC-85086]
- [N01-HC-35129]
- [N01 HC-15103]
- [N01-HC-55222]
- [N01-HC-75150]
- [N01-HC-45133]
- [HL087652]
- DIVISION OF EPIDEMIOLOGY AND CLINICAL APPLICATIONS [N01HC085079, N01HC055222, N01HC045133, N01HC035129, N01HC075150, N01HC085086, N01HC015103] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [UL1TR001079] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [U01HL080295, R01HL087652, R01HL071862, R01HL080295] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R01AG027058, R56AG020098, R01AG015928, R56AG023629, P30AG021334, R01AG023629, R01AG020098, R01AG027236] Funding Source: NIH RePORTER
- National Institute on Minority Health and Health Disparities [R01MD009164] Funding Source: NIH RePORTER
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Activation of inflammatory pathways measured by serum inflammatory markers such as interleukin-18 (IL-18) and interleukin-1 receptor antagonist (IL-1ra) is strongly associated with the progression of chronic disease states in older adults. Given that these serum cytokine levels are in part a heritable trait, genetic variation may predict increased serum levels. Using the Cardiovascular Health Study and InCHIANTI cohorts, a genome-wide association study was performed to identify genetic variants that influence IL-18 and IL-1ra serum levels among older adults. Multiple linear regression models characterized the association between each SNP and log-transformed cytokine values. Tests for multiple independent signals within statistically significant loci were performed using haplotype analysis and regression models conditional on lead SNP in each region. Multiple SNPs were associated with these cytokines with genome-wide significance, including SNPs in the IL-18-BCO gene region of chromosome 2 for IL-18 (top SNP rs2250417, P=1.9 x 10(-32)) and in the IL-1 gene family region of chromosome 2 for IL-1ra (rs6743376, P=2.3 x 10(-26)). Haplotype tests and conditional linear regression models showed evidence of multiple independent signals in these regions. Serum IL-18 levels were also associated with a region on chromosome 2 containing the NLRC4 gene (rs12989936, P = 2.7 x 10(-19)). These data characterize multiple robust genetic signals that influence IL-18 and IL-1ra cytokine production. In particular, the signal for serum IL-18 located on chromosome two is novel and potentially important in inflammasome triggered chronic activation of inflammation in older adults. Replication in independent cohorts is an important next step, as well as molecular studies to better understand the role of NLRC4. (C) 2013 Elsevier Ltd. All rights reserved.
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