The blood metabolome of incident kidney cancer: A case-control study nested within the MetKid consortium

BackgroundExcess bodyweight and related metabolic perturbations have been implicated in kidney cancer aetiology, but the specific molecular mechanisms underlying these relationships are poorly understood. In this study, we sought to identify circulating metabolites that predispose kidney cancer and to evaluate the extent to which they are influenced by body mass index (BMI). Methods and findingsWe assessed the association between circulating levels of 1,416 metabolites and incident kidney cancer using pre-diagnostic blood samples from up to 1,305 kidney cancer case-control pairs from 5 prospective cohort studies. Cases were diagnosed on average 8 years after blood collection. We found 25 metabolites robustly associated with kidney cancer risk. In particular, 14 glycerophospholipids (GPLs) were inversely associated with risk, including 8 phosphatidylcholines (PCs) and 2 plasmalogens. The PC with the strongest association was PC ae C34:3 with an odds ratio (OR) for 1 standard deviation (SD) increment of 0.75 (95% confidence interval [CI]: 0.68 to 0.83, p = 2.6 x 10(-8)). In contrast, 4 amino acids, including glutamate (OR for 1 SD = 1.39, 95% CI: 1.20 to 1.60, p = 1.6 x 10(-5)), were positively associated with risk. Adjusting for BMI partly attenuated the risk association for some-but not all-metabolites, whereas other known risk factors of kidney cancer, such as smoking and alcohol consumption, had minimal impact on the observed associations. A mendelian randomisation (MR) analysis of the influence of BMI on the blood metabolome highlighted that some metabolites associated with kidney cancer risk are influenced by BMI. Specifically, elevated BMI appeared to decrease levels of several GPLs that were also found inversely associated with kidney cancer risk (e.g., -0.17 SD change [ss(BMI)] in 1-(1-enyl-palmitoyl)-2-linoleoyl-GPC (P-16:0/18:2) levels per SD change in BMI, p = 3.4 x 10(-5)). BMI was also associated with increased levels of glutamate (ss(BMI): 0.12, p = 1.5 x 10(-3)). While our results were robust across the participating studies, they were limited to study participants of European descent, and it will, therefore, be important to evaluate if our findings can be generalised to populations with different genetic backgrounds. ConclusionsThis study suggests a potentially important role of the blood metabolome in kidney cancer aetiology by highlighting a wide range of metabolites associated with the risk of developing kidney cancer and the extent to which changes in levels of these metabolites are driven by BMI-the principal modifiable risk factor of kidney cancer. Author summary Why was this study done? Several modifiable risk factors have been established for kidney cancer, among which elevated body mass index (BMI) and obesity are central.The biological mechanisms underlying these relationships are poorly understood, but obesity-related metabolic perturbations may be important. What did the researchers do and find? We looked at the association between kidney cancer and the levels of 1,416 metabolites measured in blood on average 8 years before the disease onset. The study included 1,305 kidney cancer cases and 1,305 healthy controls.We found 25 metabolites robustly associated with kidney cancer risk.Specifically, multiple glycerophospholipids (GPLs) were inversely associated with risk, while several amino acids were positively associated with risk.Accounting for BMI highlighted that some-but not all-metabolites associated with kidney cancer risk are influenced by BMI. What do these findings mean? These findings illustrate the potential utility of prospectively measured metabolites in helping us to understand the aetiology of kidney cancer.By examining overlap between the metabolomic profile of prospective risk of kidney cancer and that of modifiable risk factors for the disease-in this case BMI-we can begin to identify biological pathways relevant to disease onset.