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Genetic variation in the TNF/TRAF2/ASK1/p38 kinase signaling pathway as markers for postoperative pulmonary complications in lung cancer patients.

Hildebrandt MA, Roth JA, Vaporciyan AA, Pu X, Ye Y, Correa AM, Kim JY, Swisher SG, Wu X - Sci Rep (2015)

Bottom Line: MAP2K4:rs12452497 was significantly associated with a decreased risk in both phases, resulting in a 40% reduction in the pooled population (95% CI:0.43-0.83, P = 0.0018).In total, seven variants were significant for risk in the pooled analysis.An inverse relationship was observed between association with clinical outcomes and complications for two variants.

View Article: PubMed Central - PubMed

Affiliation: Departments of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX.

ABSTRACT
Post-operative pulmonary complications are the most common morbidity associated with lung resection in non-small cell lung cancer (NSCLC) patients. The TNF/TRAF2/ASK1/p38 kinase pathway is activated by stress stimuli and inflammatory signals. We hypothesized that genetic polymorphisms within this pathway may contribute to risk of complications. In this case-only study, we genotyped 173 germline genetic variants in a discovery population of 264 NSCLC patients who underwent a lobectomy followed by genotyping of the top variants in a replication population of 264 patients. Complications data was obtained from a prospective database at MD Anderson. MAP2K4:rs12452497 was significantly associated with a decreased risk in both phases, resulting in a 40% reduction in the pooled population (95% CI:0.43-0.83, P = 0.0018). In total, seven variants were significant for risk in the pooled analysis. Gene-based analysis supported the involvement of TRAF2, MAP2K4, and MAP3K5 as mediating complications risk and a highly significant trend was identified between the number of risk genotypes and complications risk (P = 1.63 × 10(-8)). An inverse relationship was observed between association with clinical outcomes and complications for two variants. These results implicate the TNF/TRAF2/ASK1/p38 kinase pathway in modulating risk of pulmonary complications following lobectomy and may be useful biomarkers to identify patients at high risk.

No MeSH data available.


Related in: MedlinePlus

Potential higher-order gene-gene interactions among TNF/TRAF2/ASK1/p38 kinase signaling pathway variants.Abbreviations: C = common allele, V = variant allele.
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f1: Potential higher-order gene-gene interactions among TNF/TRAF2/ASK1/p38 kinase signaling pathway variants.Abbreviations: C = common allele, V = variant allele.

Mentions: We investigated whether there were interactions among the seven variants showing main effects in the pooled population that further modulated risk of complications. Indeed, potential higher-order interactions were observed with the initial split in the tree for TRAF2:rs6560652 with additional splits dictated by MAP2K4:rs12452497, MAP3K5:rs13195420, and TNF:rs1800629 (Fig. 1). The lowest risk nodes serving as the reference groups for the analysis were defined by the common genotype for TRAF2:rs6560652 (Node 2) and variant-containing genotypes for TRAF2:rs6560652 along with two variant alleles for the protective MAP2K4:rs12452497 variant (Node 1; Table 4). Individuals with the genetic background characterized by nodes 4 and 5 had the highest risk at nearly 4-fold (OR:3.95, 95% CI:2.34–6.34, P = 1.47 × 10−7), with over 50% of these individuals having a pulmonary complication. This increase in risk was much higher than that conferred by any individual SNP.


Genetic variation in the TNF/TRAF2/ASK1/p38 kinase signaling pathway as markers for postoperative pulmonary complications in lung cancer patients.

Hildebrandt MA, Roth JA, Vaporciyan AA, Pu X, Ye Y, Correa AM, Kim JY, Swisher SG, Wu X - Sci Rep (2015)

Potential higher-order gene-gene interactions among TNF/TRAF2/ASK1/p38 kinase signaling pathway variants.Abbreviations: C = common allele, V = variant allele.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4499815&req=5

f1: Potential higher-order gene-gene interactions among TNF/TRAF2/ASK1/p38 kinase signaling pathway variants.Abbreviations: C = common allele, V = variant allele.
Mentions: We investigated whether there were interactions among the seven variants showing main effects in the pooled population that further modulated risk of complications. Indeed, potential higher-order interactions were observed with the initial split in the tree for TRAF2:rs6560652 with additional splits dictated by MAP2K4:rs12452497, MAP3K5:rs13195420, and TNF:rs1800629 (Fig. 1). The lowest risk nodes serving as the reference groups for the analysis were defined by the common genotype for TRAF2:rs6560652 (Node 2) and variant-containing genotypes for TRAF2:rs6560652 along with two variant alleles for the protective MAP2K4:rs12452497 variant (Node 1; Table 4). Individuals with the genetic background characterized by nodes 4 and 5 had the highest risk at nearly 4-fold (OR:3.95, 95% CI:2.34–6.34, P = 1.47 × 10−7), with over 50% of these individuals having a pulmonary complication. This increase in risk was much higher than that conferred by any individual SNP.

Bottom Line: MAP2K4:rs12452497 was significantly associated with a decreased risk in both phases, resulting in a 40% reduction in the pooled population (95% CI:0.43-0.83, P = 0.0018).In total, seven variants were significant for risk in the pooled analysis.An inverse relationship was observed between association with clinical outcomes and complications for two variants.

View Article: PubMed Central - PubMed

Affiliation: Departments of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX.

ABSTRACT
Post-operative pulmonary complications are the most common morbidity associated with lung resection in non-small cell lung cancer (NSCLC) patients. The TNF/TRAF2/ASK1/p38 kinase pathway is activated by stress stimuli and inflammatory signals. We hypothesized that genetic polymorphisms within this pathway may contribute to risk of complications. In this case-only study, we genotyped 173 germline genetic variants in a discovery population of 264 NSCLC patients who underwent a lobectomy followed by genotyping of the top variants in a replication population of 264 patients. Complications data was obtained from a prospective database at MD Anderson. MAP2K4:rs12452497 was significantly associated with a decreased risk in both phases, resulting in a 40% reduction in the pooled population (95% CI:0.43-0.83, P = 0.0018). In total, seven variants were significant for risk in the pooled analysis. Gene-based analysis supported the involvement of TRAF2, MAP2K4, and MAP3K5 as mediating complications risk and a highly significant trend was identified between the number of risk genotypes and complications risk (P = 1.63 × 10(-8)). An inverse relationship was observed between association with clinical outcomes and complications for two variants. These results implicate the TNF/TRAF2/ASK1/p38 kinase pathway in modulating risk of pulmonary complications following lobectomy and may be useful biomarkers to identify patients at high risk.

No MeSH data available.


Related in: MedlinePlus