title: Novel gene variants predict serum levels of the cytokines IL-18 and IL-1ra in older adults.
abstract: 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=1.9×10(-32)) and in the IL-1 gene family region of chromosome 2 for IL-1ra (rs6743376, P=2.3×10(-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=2.7×10(-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.
authors.affiliation: Division of Geriatric Medicine, Johns Hopkins Medical Institution, Baltimore, MD, USA. Electronic address: amatteini@jhmi.edu.
authors.forename: A M
authors.initials: AM
authors.lastname: Matteini
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: E M
authors.initials: EM
authors.lastname: Lange
authors.forename: T
authors.initials: T
authors.lastname: Tanaka
authors.forename: L A
authors.initials: LA
authors.lastname: Lange
authors.forename: R P
authors.initials: RP
authors.lastname: Tracy
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: M L
authors.initials: ML
authors.lastname: Biggs
authors.forename: D E
authors.initials: DE
authors.lastname: Arking
authors.forename: M D
authors.initials: MD
authors.lastname: Fallin
authors.forename: A
authors.initials: A
authors.lastname: Chakravarti
authors.forename: B M
authors.initials: BM
authors.lastname: Psaty
authors.forename: S
authors.initials: S
authors.lastname: Bandinelli
authors.forename: L
authors.initials: L
authors.lastname: Ferrucci
authors.forename: A P
authors.initials: AP
authors.lastname: Reiner
authors.forename: J D
authors.initials: JD
authors.lastname: Walston
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics*; D002135:Calcium-Binding Proteins / Q000235:genetics*; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007249:Inflammation / Q000276:immunology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000097:blood* / Q000235:genetics*; D020382:Interleukin-18 / Q000097:blood* / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide
chemical_list: D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D020382:Interleukin-18; C435692:NLRC4 protein, human
keywords: Chronic inflammation; Genome-wide association studies; Older adults