Inflammation and stress-related candidate genes, plasma interleukin-6 levels, and longevity in older adults.

Authors: Walston JD; Matteini AM; Nievergelt C; Lange LA; Fallin DM; Barzilai N; Ziv E; Pawlikowska L; Kwok P; Cummings SR; Kooperberg C; LaCroix A; Tracy RP; Atzmon G; Lange EM; Reiner AP

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.

Keywords: Aged; Aged, 80 and over; Aging/genetics; Cardiovascular Diseases/*blood/genetics/mortality; Case-Control Studies; Female; Genetic Variation; Genotype; Humans; Inflammation/*blood/genetics/mortality; Interleukin-6/*blood/genetics; Longevity/genetics; Male; Phenotype; Poly(ADP-ribose) Polymerases/*blood/genetics; Risk Factors
Journal: Experimental gerontology
Volume: 44
Issue: 5
Pages: 350-5
Date: March 3, 2009
PMID: 19249341
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Walston JD, Matteini AM, Nievergelt C, Lange LA, Fallin DM, Barzilai N, Ziv E, Pawlikowska L, Kwok P, Cummings SR, Kooperberg C, LaCroix A, Tracy RP, Atzmon G, Lange EM, Reiner AP (2009) Inflammation and stress-related candidate genes, plasma interleukin-6 levels, and longevity in older adults. Experimental gerontology 44: 350-5.

Longevity Variant Associations (p-value):
  • rs1805415 (0.001)
  • rs4537545 (3e-18)

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