3.2. Candidate gene SNP associations with IL-0.101 0.013 3 3x1 10^(18) rs8192284 IL6R 1 152693594 Ala358Asp 0.35 HapMap SNP 0.96 rs4553185 IL6R 1 152677579 Intron 0.43 Tag SNP 0.082 0.013 3 3x1 10^(10) rs4845618 IL6R 1 152666639 Intron 0.43 Typed SNP 0.96 0.078 0.013 3 3x1 10^(10) rs4072391 IL6R 1 152705504 3' UTR 0.19 Tag SNP 0.076 0.0175x10^(6) rs2229238 IL6R 1 152704520 3' UTR 0.19 Typed SNP 0.98   (p-value <10^(15)). 
Notably, IL6R rs4537545 tags another IL6R SNP rs8192284, which encodes a functional Ala358Asp polymorphism (Table 3). 
The minor allele of PARP1 rs1805415 (which encodes a synonymous coding SNP) was associated with an increase of approximately18% in mean log IL-6 levels.
PARP1 rs1805415 is in strong linkage disequilibrium with rs1136410, which encodes a non-synonymous Val762Ala amino acid substitution.
Overall, the IL6R genotype explained2% of the inter-individual variation in the IL-6 phenotype among European American individuals, while the PARP1 genotype explained only0.2%. 
By comparison, age, sex, clinic, BMI, and smoking explained12% of the IL-6 phenotypic variance.
The odds ratio for the minor allele of PARP1 rs1805415 was0.75 (95%CI 0.56-0.99; p = 0.04) in CHS European American individuals. In contrast, there was no association between PARP1 rs1805415 among SOF longevity cases and controls (odds ratio = 1.02; 95%CI 0.77-1.36; p = 0.88).
There was no evidence that the association between PARP1 rs1805415 and longevity differed by gender in either CHS or the Ashkenazi Jews (data not shown).
In the pooled analysis of all three studies, the risk of longevity associated with the minor allele of PARP1 rs1805415 was 0.79 (95%CI 0.67-0.92; p = 0.003) under a fixed-effect model.
Under a random-effect model, the pooled odds ratio was 0.79 (95%CI 0.62-1.02; p = 0.07), with an estimate of between-study variance of 0.03.
Seven other SNPs nominally associated with longevity in CHS (p < 0.02) showed little evidence of association with longevity in either SOF or the Ashkenazi Jewish centenarian study (Supplemental Table 4).
In European American individuals, tagSNPs within several genes encoding components of the nuclear factor kappa B (NF-kB) transcription factor complex (IKBKE, IKBKB, and RELA) or the IL-6 signal transducer and activator of transcription-3 gene (STAT3) showed weaker evidence of association with IL-6 phenotype (Supplemental Table 2).
Among the smaller CHS African American cohort, an intronic SNP within the Toll-like receptor 4 gene (TLR4) had a borderline association with higher IL-6 levels (q-value = 0.07).
Several additional tagSNPs of IL6R, STAT3, or IL6ST (which encodes the IL-6 signal transducer component of the IL-6 receptor complex) showed weaker evidence of association with IL-6 phenotype among African Americans (Supplemental Table 3).
Our results confirm that higher circulating IL-6 levels strongly predict future mortality in a large community-based sample of older European American and African American adults from CHS.
By screening a panel of inflammation and stress-response candidate genes, we demonstrate that SNPs tagging common functional polymorphisms of IL6R and PARP1 are associated with circulating IL-6 levels among European American CHS participants.
Though no SNPs contained within our candidate gene panel reached the experiment-wide significance threshold of association with longevity in our screening analysis, it is noteworthy that the minor allele of PARP1 rs1805415, which was significantly associated with higher baseline IL-6 levels (an important longevity endo-phenotype), was nominally associated with decreased longevityThe National Institute on Aging Claude D. Pepper Older Americans Independence Centers provided support for this study, along with grants R01 AG027236 (Dr. Walston), R01 HL-071862 (Dr. Reiner), R01 HL077449 (Dr. Tracy), P01 AG027734 (Dr. Atzmon) and U01 HL080295 from the NHLBI, and additional funding from the National Institute of Neurological Disorders and Stroke. A complete list of participating CHS investigators and institutions can be found at http://www.chs-nhlbi.org. Genotyping services for CHS were provided by the Center for Inherited Disease Research (CIDR), which is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, Contract Number N01-HG-65403. Genotyping services for CHS were also provided by the Johns Hopkins University under federal contract number (N01-HV-48195) from the National Heart, Lung, and Blood Institute. We used public re-sequencing data from the SeattleSNPs program, supported by NIH U01 HL66682 (http://www.pga.gs.washington.edu/). This work was also supported by grants from the Paul Beeson Physician Faculty Scholar in Aging Award, the Ellison Medical Foundation Senior Scholar Award, NIH RO1 (AG-18728).