title: Inflammation and stress-related candidate genes, plasma interleukin-6 levels, and longevity in older adults.
abstract: Interleukin-6 (IL-6) is an inflammatory cytokine that influences the development of inflammatory and aging-related disorders and ultimately longevity. In order to study the influence of variants in genes that regulate inflammatory response on IL-6 levels and longevity, we screened a panel of 477 tag SNPs across 87 candidate genes in >5000 older participants from the population-based Cardiovascular Health Study (CHS). Baseline plasma IL-6 concentration was first confirmed as a strong predictor of all-cause mortality. Functional alleles of the IL6R and PARP1 genes were significantly associated with 15%-20% higher baseline IL-6 concentration per copy among CHS European-American (EA) participants (all p<10(-4)). In a case/control analysis nested within this EA cohort, the minor allele of PARP1 rs1805415 was nominally associated with decreased longevity (p=0.001), but there was no evidence of association between IL6R genotype and longevity. The PARP1 rs1805415--longevity association was subsequently replicated in one of two independent case/control studies. In a pooled analysis of all three studies, the "risk" of longevity associated with the minor allele of PARP1 rs1805415 was 0.79 (95%CI 0.62-1.02; p=0.07). These findings warrant further study of the potential role of PARP1 genotype in inflammatory and aging-related phenotypes.
authors.affiliation: Johns Hopkins Medical Institutions, Johns Hopkins University, John R Burton Pavilion, 5505 Hopkins Bayview Circle, Baltimore, MD 21224, USA. jwalston@jhmi.edu
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Walston
authors.forename: Amy M
authors.initials: AM
authors.lastname: Matteini
authors.forename: Caroline
authors.initials: C
authors.lastname: Nievergelt
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Lange
authors.forename: Dani M
authors.initials: DM
authors.lastname: Fallin
authors.forename: Nir
authors.initials: N
authors.lastname: Barzilai
authors.forename: Elad
authors.initials: E
authors.lastname: Ziv
authors.forename: Ludmila
authors.initials: L
authors.lastname: Pawlikowska
authors.forename: Pui
authors.initials: P
authors.lastname: Kwok
authors.forename: Steve R
authors.initials: SR
authors.lastname: Cummings
authors.forename: Charles
authors.initials: C
authors.lastname: Kooperberg
authors.forename: Andrea
authors.initials: A
authors.lastname: LaCroix
authors.forename: Russell P
authors.initials: RP
authors.lastname: Tracy
authors.forename: Gil
authors.initials: G
authors.lastname: Atzmon
authors.forename: Ethan M
authors.initials: EM
authors.lastname: Lange
authors.forename: Alex P
authors.initials: AP
authors.lastname: Reiner
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics; D002318:Cardiovascular Diseases / Q000097:blood* / Q000235:genetics / Q000401:mortality; D016022:Case-Control Studies; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007249:Inflammation / Q000097:blood* / Q000235:genetics / Q000401:mortality; D015850:Interleukin-6 / Q000097:blood* / Q000235:genetics; D008136:Longevity / Q000235:genetics; D008297:Male; D010641:Phenotype; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000097:blood* / Q000235:genetics; D012307:Risk Factors
chemical_list: D015850:Interleukin-6; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases