The Association of a Variant in the Cell Cycle Control Gene CCND1 and Obesity on the Development of Asthma in the Swiss SAPALDIA Study

Abstract

Objective. The molecular mechanisms underlying the association between obesity (BMI ≥ 30 kg/m²) and asthma are poorly understood. Since shifts in the fate of bronchial cells due to low-grade systemic inflammation may provide a possible explanation, we investigated whether two of the best documented functional variants in cell cycle control genes modify the obesity–asthma association. Methods. We genotyped 5930 SAPALDIA cohort participants for the single-nucleotide polymorphisms (SNPs) rs9344 in the cyclin D1 gene (CCND1) and rs1042522 in the gene encoding tumor protein 53 (TP53). We assessed the independent association of these SNPs and obesity with asthma prevalence and incidence. Results. The CCND1 SNP modified the association between obesity and asthma prevalence (p_interaction = 0.03). The odds ratios (ORs) and 95% confidence intervals (CIs) for reporting a physician diagnosis of asthma at baseline, comparing obese with non-obese participants, were 1.09 (0.51–2.33), 1.64 (0.94–2.88), and 3.51 (1.63–7.53) for GG, GA, and AA genotypes, respectively. We found comparable genotype differences for incident asthma within the 11 years of follow-up. As for the TP53 SNP, the interactions with obesity status with respect to asthma were not statistically significant. Conclusions. Our results suggest that obesity may contribute to asthma and associated tissue remodeling by modifying the processes related to the CCND1 gene activity.

• candidate gene association study
• cell proliferation genes
• gene–lifestyle interaction
• overweight
• population-based cohort
• single-nucleotide polymorphism

Acknowledgments

The authors thank the following: The SAPALDIA team; study directorate: T Rochat (p), JM Gaspoz (c), N Künzli (e/exp), LJS Liu (exp), NM Probst-Hensch (e/g), C Schindler (s). Scientific team: JC Barthélémy (c), W Berger (g), R Bettschart (p), A Bircher (a), G Bolognini (p), O Brändli (p), C Brombach (n), M Brutsche (p), L Burdet (p), M Frey (p), U Frey (pd), MW Gerbase (p), D Gold (e/c/p), E de Groot (c), W Karrer (p), R Keller (p), B Knöpfli (p), B Martin (pa), D Miedinger (o), U Neu (exp), L Nicod (p), M Pons (p), F Roche (c), T Rothe (p), E Russi (p), P Schmid-Grendelmeyer (a), A Schmidt-Trucksäss (pa), A Turk (p), J Schwartz (e), D. Stolz (p), P Straehl (exp), JM Tschopp (p), A von Eckardstein (cc), E Zemp Stutz (e). Scientific team at coordinating centers: M Adam (e/g), E Boes (g), PO Bridevaux (p), D Carballo (c), E Corradi (e), I Curjuric (e), J Dratva (e), A Di Pasquale (s), L Grize (s), D Keidel (s), S Kriemler (pa), A Kumar (g), M Imboden (g), N Maire (s), A Mehta (e), F Meier (e), H Phuleria (exp), E Schaffner (s), GA Thun (g) A Ineichen (exp), M Ragettli (exp), M Ritter (exp), T Schikowski (e), G Stern (pd), M Tarantino (s), M Tsai (exp), M Wanner (pa). (a) 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. Administrative staff: C Gabriel, R Gutknecht. 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, A Walder.

The authors declare that they have no competing interests.

SAPALDIA is supported by the Swiss National Science Foundation (grants no, 3247BO-104283, 3247BO-104288, 3247BO-104284, 3247–065896, 3100–059302, 3200–052720, 3200–042532, 4026–028099, 3233–054996, PDFMP3-123171), the Federal Office for Forest, Environment and Landscape, 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, Zurich, the Swiss Lung League, the canton’s Lung League of Basel Stadt/ Basel Landschaft, Geneva, Ticino, Valais and Zurich, SUVA, Freiwillige Akademische Gesellschaft, UBS Wealth Foundation, Talecris Biotherapeutics GmbH, Abbott Diagnostics, European Commission 018996 (GABRIEL), Wellcome Trust WT 084703MA.