Bull, Caroline J

Corbin, Laura J

Guida, Florence

Johansson, Mattias

Tan, Y

Timpson, Nicholas John

Vincent, Emma E

English

Background: Excess 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 Findings: We 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 five prospective cohort studies. Cases were diagnosed on average eight years after blood collection. We found 25 metabolites robustly associated with kidney cancer risk. In particular, 14 glycerophospholipids (GPL) were inversely associated with risk, including eight phosphatidylcholines (PC) and two plasmalogens. The PC with the strongest association was PC ae C34:3 with an odds-ratio (OR) for one standard deviation (SD) increment of 0.75 (95% CI: 0.68 to 0.83, p=2.6x10-8). In contrast, four amino acids, including glutamate (OR for 1 SD=1.39, 95% CI: 1.20 - 1.60, p=1.6x10-5), 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 randomization 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 standard deviation change [ßBMI] in 1-(1-enyl-palmitoyl)-2-linoleoyl-GPC (P-16:0/18:2) levels per SD change in BMI, p=3.4x10-5). BMI was also associated with increased levels of glutamate (ßBMI: 0.12, p=1.5x10-3). Whilst 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 generalized to populations with different genetic backgrounds.Conclusions: This 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.<br/

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

https://research-information.bris.ac.uk/files/288763995/MainManuscript_Metkid_PlosMedicine_final_1_merged_merged_1_2_.pdf

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

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