Common SIRT1 variants modify the effect of abdominal adipose tissue on aging-related lung function decline
Lung function is an independent predictor of mortality and serves as an aging marker in never smokers. The protein sirtuin-1 of gene SIRT1 has profound anti-inflammatory effects and regulates metabolic pathways. Its suggested longevity effects on lower organisms remain poorly studied in humans. In 1132 never smokers of the population-based SAPALDIA cohort, we investigated associations between single nucleotide polymorphisms (SNPs; rs730821, rs10997868, rs10823116) of SIRT1 and aging-related lung function decline over 11 years in terms of change in forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, and forced expiratory flow between 25 and 75 % of FVC (FEF25–75) using multiple linear regression models. Interactions between the SIRT1 SNPs and adiposity parameters (body mass index (BMI), its change and weight gain) were tested by including multiplicative interaction terms into the models. SIRT1 polymorphisms exhibited no main effects, but modified the association between obesity measures and FEV1/FVC and FEF25–75 decline (p = 0.009–0.046). Per risk allele, FEV1/FVC decline was accelerated up to −0.5 % (95 % CI −1.0 to 0 %) and −0.7 % (−1.3 to −0.2 %) over interquartile range increases in BMI (2.4 kg/m2) or weight (6.5 kg), respectively. For FEF25–75 decline, corresponding estimates were −57 mL/s (−117 to 4 mL/s) and −76 mL/s (−1429 to −9 mL/s). Interactions were not present in participants with genetically lowered C-reactive protein concentrations. Genetic variation in SIRT1 might therefore affect lung function and human longevity by modifying subclinical inflammation arising from abdominal adipose tissue.
KeywordsSirtuin-1 Lung Metabolism Inflammation Cohort study Population-based
The authors acknowledge the work of the whole SAPALDIA team: Study directorate: NM Probst-Hensch (PI; e/g); T Rochat (p), C Schindler (s), N Künzli (e/exp), JM Gaspoz (c); the scientific team: JC Barthélémy (c), W Berger (g), R Bettschart (p), A Bircher (a), C Brombach (n), PO Bridevaux (p), L Burdet (p), Felber Dietrich D (e), M Frey (p), U Frey (pd), MW Gerbase (p), D Gold (e), E de Groot (c), W Karrer (p), F Kronenberg (g), B Martin (pa), A Mehta (e), D Miedinger (o), M Pons (p), F Roche (c), T Rothe (p), P Schmid-Grendelmeyer (a), D Stolz (p), A Schmidt-Trucksäss (pa), J Schwartz (e), A Turk (p), A von Eckardstein (cc), E Zemp Stutz (e); and the scientific team at coordinating centers: M Adam (e), I Aguilera (exp), S Brunner (s), D Carballo (c), S Caviezel (pa), I Curjuric (e), A Di Pascale (s), J Dratva (e), R Ducret (s), E Dupuis Lozeron (s), M Eeftens (exp), I Eze (e), E Fischer (g), M Foraster (e), M Germond (s), L Grize (s), S Hansen (e), A Hensel (s), M Imboden (g), A Ineichen (exp), A Jeong (g), D Keidel (s), A Kumar (g), N Maire (s), A Mehta (e), R Meier (exp), E Schaffner (s), T Schikowski (e), M Tsai (exp).
The study could not have been done without the help of the study participants, technical and administrative support, and the medical teams and field workers at the local study sites. Local fieldworkers: Aarau: S Brun, G Giger, M Sperisen, M Stahel, Basel: C Bürli, C Dahler, N Oertli, I Harreh, F Karrer, G Novicic, N Wyttenbacher, Davos: A Saner, P Senn, R Winzeler, Geneva: F Bonfils, B Blicharz, C Landolt, J Rochat, Lugano: S Boccia, E Gehrig, MT Mandia, G Solari, B Viscardi, Montana: AP Bieri, C Darioly, M Maire, Payerne: F Ding, P Danieli A Vonnez, Wald: D Bodmer, E Hochstrasser, R Kunz, C Meier, J Rakic, U Schafroth, and A Walder; administrative staff: N Bauer Ott, C Gabriel, and R Gutknecht.
(a) corresponds to allergology, (c) cardiology, (cc) clinical chemistry, (e) epidemiology, (exp) exposure, (g) genetic and molecular biology, (m) meteorology, (n) nutrition, (o) occupational health, (p) pneumology, (pa) physical activity, (pd) pediatrics, (s) statistics.
Compliance with ethical standards
All study participants gave written informed consent, and the study was approved by the Swiss Academy of Medical Sciences as well as the respective regional ethics committees.
This work was supported by the Swiss National Science Foundation (grant nos. 33CS30-148470/1, 33CSCO-134276/1, 33CSCO-108796, 324730_135673, 3247BO-104283, 3247BO-104288, 3247BO-104284, 3247-065896, 3100-059302, 3200-052720, 3200-042532, 4026-028099, PMPDP3_129021/1, PMPDP3_141671/1); the Federal Office for the Environment; the Federal Office of Public Health; the Federal Office of Roads and Transport; the canton’s government of Aargau, Basel-Stadt, Basel-Land, Geneva, Luzern, Ticino, Valais, and Zürich; the Swiss Lung League; the canton’s Lung League of Basel Stadt/ Basel Landschaft, Geneva, Ticino, Valais, Graubünden, and Zurich; Stiftung ehemals Bündner Heilstätten; SUVA; Freiwillige Akademische Gesellschaft; UBS Wealth Foundation; Talecris Biotherapeutics GmbH; Abbott Diagnostics; European Commission 018996 (GABRIEL), and Wellcome Trust WT 084703MA.
- American Thoracic Society (1987) Standardization of spirometry—1987 update. Statement of the American Thoracic Society. Am Rev Respir Dis 136:1285–1298Google Scholar
- Bigaard J, Frederiksen K, Tjonneland A, Thomsen BL, Overvad K, Heitmann BL, TI Sorensen (2005) Waist circumference and body composition in relation to all-cause mortality in middle-aged men and women. Int J Obes 29:778–784 doi:10.1038/sj.ijo.0802976.
- Hwang JW, Chung S, Sundar IK, Yao H, Arunachalam G, McBurney MW, Rahman I (2010) Cigarette smoke-induced autophagy is regulated by SIRT1-PARP-1-dependent mechanism: implication in pathogenesis of COPD. Arch Biochem Biophys 500:203–209. doi:10.1016/j.abb.2010.05.013 CrossRefPubMedPubMedCentralGoogle Scholar
- International HapMap Consortium (2005) A haplotype map of the human genome. Nature 437:1299–1320. doi:10.1038/nature04226
- Schunemann HJ, Dorn J, Grant BJ, W Winkelstein. Jr., Trevisan M (2000) Pulmonary function is a long-term predictor of mortality in the general population: 29-year follow-up of the Buffalo Health Study. Chest 118:656–664.Google Scholar