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Novel gene variants predict serum levels of the cytokines IL-18 and IL-1ra in older adults.
Tuesday,2013-11-05 11:20 America/Los_Angeles — poolea2
| Title | Novel gene variants predict serum levels of the cytokines IL-18 and IL-1ra in older adults. |
| Publication Type | Journal Article |
| Year of Publication | 2014 |
| Authors | Matteini, AM, Li, J, Lange, EM, Tanaka, T, Lange, LA, Tracy, RP, Wang, Y, Biggs, ML, Arking, DE, Fallin, MD, Chakravarti, A, Psaty, BM, Bandinelli, S, Ferrucci, L, Reiner, AP, Walston, JD |
| Journal | Cytokine |
| Volume | 65 |
| Issue | 1 |
| Pagination | 10-6 |
| Date Published | 2014 Jan |
| ISSN | 1096-0023 |
| Keywords | Aged, Aged, 80 and over, Calcium-Binding Proteins, CARD Signaling Adaptor Proteins, Chromosomes, Human, Pair 2, Female, Genetic Variation, Genome-Wide Association Study, Genotype, Haplotypes, Humans, Inflammation, Interleukin 1 Receptor Antagonist Protein, Interleukin-18, Male, Polymorphism, Single Nucleotide |
| Abstract | <p>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. </p> |
| DOI | 10.1016/j.cyto.2013.10.002 |
| Alternate Journal | Cytokine |
| PubMed ID | 24182552 |
| PubMed Central ID | PMC4060632 |
| Grant List | R01 AG027236 / AG / NIA NIH HHS / United States R01 AG015928 / AG / NIA NIH HHS / United States U01 HL080295 / HL / NHLBI NIH HHS / United States UL1 TR001079 / TR / NCATS NIH HHS / United States R01 MD009164 / MD / NIMHD NIH HHS / United States N01 HC015103 / HC / NHLBI NIH HHS / United States R56 AG020098 / AG / NIA NIH HHS / United States P30 AG021334 / AG / NIA NIH HHS / United States R01 HL087652 / HL / NHLBI NIH HHS / United States AG-20098 / AG / NIA NIH HHS / United States HL087652 / HL / NHLBI NIH HHS / United States N01HC55222 / HL / NHLBI NIH HHS / United States N01-HC-85086 / HC / NHLBI NIH HHS / United States N01HC85086 / HL / NHLBI NIH HHS / United States AG-027058 / AG / NIA NIH HHS / United States HHSN268201200036C / HL / NHLBI NIH HHS / United States N01-HC-55222 / HC / NHLBI NIH HHS / United States N01-HC-75150 / HC / NHLBI NIH HHS / United States R01 HL071862 / HL / NHLBI NIH HHS / United States R01 HL080295 / HL / NHLBI NIH HHS / United States R01 AG020098 / AG / NIA NIH HHS / United States N01HC75150 / HL / NHLBI NIH HHS / United States N01-HC-85079 / HC / NHLBI NIH HHS / United States HHSN268201200036C / / PHS HHS / United States HL080295 / HL / NHLBI NIH HHS / United States N01-HC-85239 / HC / NHLBI NIH HHS / United States AG-023629 / AG / NIA NIH HHS / United States N01HC85079 / HL / NHLBI NIH HHS / United States R01 AG023629 / AG / NIA NIH HHS / United States R01 AG027058 / AG / NIA NIH HHS / United States N01 HC045133 / HC / NHLBI NIH HHS / United States N01 HC035129 / HC / NHLBI NIH HHS / United States R56 AG023629 / AG / NIA NIH HHS / United States |