Inflammation and stress-related candidate genes, plasma interleukin-6 levels, and longevity in older adults.
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.
Walston
Jeremy D
JD
Johns Hopkins Medical Institutions, Johns Hopkins University, John R Burton Pavilion, 5505 Hopkins Bayview Circle, Baltimore, MD 21224, USA. jwalston@jhmi.edu
Matteini
Amy M
AM
Nievergelt
Caroline
C
Lange
Leslie A
LA
Fallin
Dani M
DM
Barzilai
Nir
N
Ziv
Elad
E
Pawlikowska
Ludmila
L
Kwok
Pui
P
Cummings
Steve R
SR
Kooperberg
Charles
C
LaCroix
Andrea
A
Tracy
Russell P
RP
Atzmon
Gil
G
Lange
Ethan M
EM
Reiner
Alex P
AP
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
D015850:Interleukin-6; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases