Acknowledgments

The observed IL6R genotype – IL6 phenotype association in confirms recent findings from several other studies of middle-aged and older adults, including the Health Study (WHS) (Qi et al., 2007), the InCHIANTI Italian (Rafiq et al., 2007), and the Health ABC cohort (Reich et al., Based on the HapMap data base, the IL6R tagSNP rs4537545 ing the strongest association with plasma IL-6 levels in CHS is linkage disequilibrium (r2 > 0.8) with at least seven other IL6R SNPs among Europeans; these include rs8192284, which codes a functional Ala358Asp non-synonymous amino acid tution located at the site where the IL-6 receptor is cleaved to soluble IL-6 receptor (sIL-6R) (Galicia et al., 2004; Reich et 2007). The IL6R rs8192284 Ala358Asp polymorphism has associated with higher sIL-6R levels in Health ABC and explaining a substantial part of sIL-6R phenotypic variance et al., 2007; Rafiq et al., 2007).

This study was supported by contracts N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-55222, N01 HC-15103, N01-HC-75150, N01-HC-45133, Grant No. U01 HL080295 from the National Heart, Lung, and Blood Institute, U19 AG023122 from the National Institute on Aging Longevity Consortium and P30 AG021334 from the National Institute on Aging Claude D. Pepper Older Americans Independence Centers, and grants R01 AG027236 (Dr. Walston), R01 HL-071862 (Dr Reiner), R01 HL077449 (Dr. Tracy), P01 AG027734 (Dr. Atzmon) and U01 HL080295 from the NHLBI, with additional contribution from the National Institute of Neurological Disorders and Stroke. A full 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). CIDR is fully funded through a federal contract from the National Insti- tutes 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 utilized public re-sequencing data from the SeattleSNPs program, supported by NIH U01 HL66682 (http://www.pga.gs.washing- ton.edu/). This work has also been supported by grants from the Paul Beeson Physician Faculty Scholar in Aging Award, the Ellison Medical Foundation Senior Scholar Award, NIH RO1 (AG-18728–

Despite the strong evidence for association with IL-6 and sIL-6R phenotypes, there was no evidence for association between IL6R genotype and longevity in CHS, nor with other systemic markers of inflammation in InCHIANTI (Rafiq et al., 2007). In fact, the IL6R rs8192284 variant allele was recently reported in a genome-wide association study from WHS (Ridker et al., 2008) to be associated with lower CRP levels, which is in the opposite direction to its re- ported effect on IL-6 and sIL-6R levels. Unlike other soluble recep- tors, sIL-6R is generally thought to act as an agonist of IL-6, thus allowing gp130-mediated IL-6 signaling to occur on cells without a membrane-bound IL-6R (so-called ‘trans-signaling’) (Jones et al., 2001; Knüpfer and Preiss, 2008). However, the biology of IL-6 signaling is complex, and can have both pro- and anti-inflam- matory effects (Gabay, 2006; Knüpfer and Preiss, 2008). These observations suggest a different mechanism of action of PARP-1 versus soluble IL-6 receptor gene variants on the expression of dis- tinct inflammatory- and aging-related phenotypes. Therefore, the association of PARP1 genotype with higher plasma levels of both CRP and IL-6 (two important inflammation/stress-response pro- teins, each of which predict mortality), as well as the probable influence of PARP-1 as a more global regulator of transcription and other genes related to aging, may account for the apparent association between PARP1 genotype and the more complex clini- cal outcome of longevity.

Appendix A. Supplementary data

Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.exger.2009.02.004.

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