The Association of a Variant in the Cell Cycle Control GeneCCND1and Obesity on the Development of Asthma in the Swiss SAPALDIA Study

Abstract

OBJECTIVE: The molecular mechanisms underlying the association between obesity (BMI 30 kg/m(2)) and asthma are poorly understood. Since shifts in the fate of bronchial cells due to lowgrade 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. Objective. The molecular mechanisms underlying the association between obesity (BMI 30 kg/m 2 ) 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 ¼ 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.of Asthma, 2013; 50(2): 147-154 Copyright © 2013 Informa Healthcare USA, Inc. ISSN: 0277-0903 print/1532-4303

Identification of Candidate Genes and Pathways Associated with Obesity-Related Traits in Canines via Gene-Set Enrichment and Pathway-Based GWAS Analysis

“…Further, Lim et al reported that the increased expression of obesity-associated molecules increases the risk of development of mammary gland tumors in obese female canines [51]. These pathways are enriched with numerous genes and in fact, the mutations in a few key genes have been described to affect obesity or blood sugar trait [12,49,[52][53][54]. In total, 64 genes were significantly enriched in cancer-related pathways and several significant genes such as cyclic AMP-responsive element-binding protein 5 (CREB5) [55], AKT serine/threonine kinase 3 (AKT3) [53], cyclin D1 (CCND1) [12,52], Wnt family member 1 (WNT1) [49,54] were identified to be associated with blood sugar and obesity traits.…”

Integrated bioinformatics analysis reveals novel key biomarkers and potential candidate small molecule drugs in gestational diabetes mellitus

“…From the miRNA-hub gene network construction and TF-hub gene network diagram, it can be observed that UBE2D3, HSP90AA1, PAK2, DDB1, DVL3, FYN, ABL1, SMAD3, STAT3, PRKCA, EGFR, PSMC4, CCND1, FOXO1, hsa-mir-6127, hsa-let-7d-5p, hsa-mir-8063, hsa-mir-329-3p, hsa-mir-1207-5p, hsa-mir-4651, hsa-mir-410-5p, hsa-mir-222-3p, hsa-mir-29c-3p, hsa-mir-663a, E2F1, HCFC1, SRY, ZFX, RUNX1, SPI1, MYBL2, SUZ12, TBX3 and YAP1 were the key nodes of the miRNA-hub gene network construction and TF-hub gene network, with the highest node degree value. Expression of the CCND1 gene plays a role in the development of obesity [189], but this gene might be associated with progression of GDM. FOXO1 [190], hsa-mir-1207-5p [191], hsa-mir-4651 [191], hsa-mir-222-3p [192] and E2F1 [193] are essential for the progression of GDM.…”

Identification of key pathways and genes in obesity using bioinformatics analysis and molecular docking studies

“…Target genes -miRNA regulatory network up regulated genes was constructed and analyzed. CCND1 was responsible for progression of obesity [209]. CCND2 was associated with development of insulin resistance [210].…”