Abstract
Biological age is an important risk factor for chronic diseases. We examined the associations between five markers of unhealthy ageing; Growth Differentiation Factor-15 (GDF-15), N-terminal pro-brain natriuretic peptide (NT-proBNP), glycated hemoglobin A1c (HbA1C), C-Reactive Protein (CRP) and cystatin-C; with risks of cancer and cardiovascular disease (CVD). We used a case-cohort design embedded in the EPIC-Heidelberg cohort, including a subcohort of 3792 participants along with 4867 incident cases of cancer and CVD. Hazard ratios (HRs) were computed and the strongest associations were used to build weighted multi-marker combinations, and their associations with cancer and CVD risks were tested. After adjusting for common confounders, we observed direct associations of GDF-15 with lung cancer risk, NT-proBNP with breast, prostate and colorectal cancers, HbA1C with lung, colorectal, and breast cancer risks, and CRP with lung and colorectal cancer risks. An inverse association was observed for GDF-15 and prostate cancer risk. We also found direct associations of all 5 markers with myocardial infarction (MI) risk, and of GDF-15, NT-proBNP, CRP and cystatin-C with stroke risk. A combination of the independently-associated markers showed a moderately strong association with the risks of cancer and CVD (HRQ4-Q1 ranged from 1.78[1.36, 2.34] for breast cancer, when combining NT-proBNP and HbA1C, to 2.87[2.15, 3.83] for MI when combining NT-proBNP, HbA1C, CRP and cystatin-C). This analysis suggests that combinations of biomarkers related to unhealthy ageing show strong associations with cancer risk, and corroborates published evidence on CVD risk. If confirmed in other studies, using these biomarkers could be useful for the identification of individuals at higher risk of age-related diseases.
Highlights
Non-communicable diseases (NCDs) are the number one cause of mortality worldwide
Our findings suggested no association between circulating growth differentiation factor-15 (GDF-15) with breast or colorectal cancer; an independent prospective study showed a positive association between GDF-15 levels and colorectal cancer risk [40]
Our results suggested that NT-proBNP and hemoglobin A1c (HbA1C) combined together, show a strong joint association with breast cancer incidence, while combining GDF-15 and HbA1C is strongly associated with lung cancer incidence
Summary
Non-communicable diseases (NCDs) are the number one cause of mortality worldwide. According to the Global Burden of Diseases (GBD), 73.4% of the deaths that occurred in 2017 were linked to NCDs, among which approximately 31% linked to cardiovascular diseases (CVD) and 29% to cancer [1]. Five major biomarkers in the selected list are: (i) growth differentiation factor-15 (GDF-15; previously known as macrophage-inhibitory cytokine-1 [MIC-1]), produced in response to oxidative stress and mitochondrial dysfunction and used as a marker for metabolic effects induced by metformin, a widely used glucose-lowering agent with a potential life-span extending effects in animal studies [17, 18]; (ii) N-terminal pro-brain natriuretic peptide (NT-proBNP), a protein secreted by ventricular myocytes to decrease vascular resistance [19] and used as biomarker for cardiovascular health, to diagnose and establish the prognosis for heart failure [20]; (iii) glycated hemoglobin A1c (HbA1C), a marker for medium-term average plasma glucose and metabolic ageing [15]; (iv) C-reactive protein (CRP), a marker for systemic inflammation [15]; and (v) cystatin-C, a biomarker of glomerular filtration rate (GFR), kidney disease and ageing-related physical and cognitive dysfunction [21]
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