A Study On The Association Between Central Carbon Metabolites And The Occurrence Of Pulmonary Nodules In A Population At High Risk Of Lung Cancer

ObjectiveWith the widespread use of LDCT technology in lung cancer screening,pulmonary nodules（PNs）have become a common finding during screening,especially in those at high risk for lung cancer.Significant changes in plasma metabolite levels,mainly amino acid metabolism and lipid metabolism,were observed in subjects with PNs in previous studies.However,the research on the association between central carbon metabolites and PNs is limited.The aim of this study was to investigate the concentrations of 16central carbon metabolites in the plasma of individuals with PNs and to explore the association of central carbon metabolism with PNs risk.MethodsFrom June to November 2020,this study was conducted with a high-risk population of lung cancer assessed at baseline（the collection of baseline data for Ma’anshan Lung Screening Cohort had been completed in the previous phase）.At baseline,data on general demographic characteristics,lifestyle and behavioral habits,personal and family history of diseases,physical measurements,LDCT reports,and early morning fasting plasma samples were collected.From June to November 2021,an experimental method for the detection of plasma central carbon metabolites was mapped and baseline plasma samples were tested by using Gas Chromatography-triple Quadrupole Mass Spectrometry,in which the concentrations of 16 plasma central carbon metabolites were detected.The inverse probability weighting technique was used to control for bias due to self-selection for LDCT in the assessed high-risk population.Logistic regression models with the individual weights in models were applied to estimate the weighted associations between central carbon metabolites and the risk of PNs.Plasma metabolite concentrations were used as classification variables to fit the models based on the quartiles,and the lowest quartiles were the reference group.ORs and 95%CIs were calculated to estimate the level of each metabolite on the risk of PNs.The LASSO regression was used to deal with complex multicollinearity data.The Quantile g-Computation model was used to assess the joint effect of metabolites and the risk of PNs.ResultsA total of 1984 participants were tested for plasma central carbon metabolite concentrations in this study,and an estimated 1954 participants were screened after inverse probability weighting.Of these participants,505 males and 199 females were detected with PNs.The mean age in the PNs group was 62.63 years old and in the non-PNs group was 62.19 years old,with no statistically significant difference in age between the two groups.The plasma concentrations of 2-ketoglutaric acid,3-hydroxybutyric acid,gluconic acid,phosphoenolpyruvic acid,succinic acid,hippuric acid,citric acid,malic acid,L-lactic acid,cis-aconitate,and isocitric acid were significantly higher in the PNs group than in the non-PNs group,and the plasma concentrations of 2-oxoadipic acid and orotic acid were significantly lower in the PNs group than in the non-PNs group,whereas there were no statistically significant differences between the two groups for the comparison of the concentrations of fumaric acid,glyceric acid,and gluconic acid.A total of eight metabolites were screened by using LASSO regression and included in the multi-metabolite model.In the multi-metabolite model,as compared to the first quantile,we found a significant negative association of 2-oxoadipic acid with the PNs risk regardless of the quantile,with ORs of 0.31,0.25 and 0.28,respectively.Although there was a positive association between gluconic acid and the risk of PNs in the other quartiles,however,the trend of this association was not significant（P-FDR>0.05）.Compared with the first quartile,both succinic acid and hippuric acid at the third and fourth quartile concentration levels increased the risk of PNs.The OR of succinic acid in the highest quartile was up to 2.20（95%CI:1.56 to 3.10）,and the OR of hippuric acid in the highest quartile was up to 2.04（95%CI:1.46 to 2.84）.The present study also found that the highest quartile concentration level of fumaric acid reduced the risk of PNs(OR _{Q4 vs Q1}=0.41,95%CI:0.28 to 0.58).The Quantile g-Computation model was used to explore the joint effect of metabolites in association with the risk of PNs.Overall,the 16 metabolite mixture was positively but not significantly associated with PNs.When the mixture of 16 metabolites was increased by one quartile,the OR of PNs was 1.10（95%CI:0.92～1.31）,P=0.30.With the largest contribution of positive weights were hippuric acid and succinic acid,and the largest contribution of negative weights were fumaric acid and 2-oxadipic acid.ConclusionsElevated levels of plasma 3-hydroxybutyric acid,gluconic acid,succinic acid,and hippuric acid concentrations significantly increased the risk of pulmonary nodules;whereas 2-oxoadipic acid and fumaric acid were negatively associated with the risk of pulmonary nodules.In this study,a positive but not significant combined effect of a mixture of 16 metabolites on pulmonary nodules was observed.Among them,hippuric acid and succinic acid contributed the most positive weight to the association with the risk of pulmonary nodule,and fumaric acid and 2-oxoadipic acid contributed the most negative weight to the association with the risk of pulmonary nodule and may serve as key metabolic pathways for pulmonary nodule intervention.Disturbances in central carbon metabolism may be a potential cause of pulmonary nodule development.