Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - BIOMENDELIAN (Linking Cardiometabolic Disease and Cancer in the Level of Genetics, Circulating Biomarkers, Microbiota and Environmental Risk Factors)

Teaser

Project name: Linking Cardiometabolic Disease and Cancer in the Level of Genetics, Circulating Biomarkers, Microbiota and Environmental Risk Factors ( BIOMENDELIAN)The problem being addressed in BIOMENDELIAN:The purpose of this proposal is to provide novel understanding of...

Summary

Project name: Linking Cardiometabolic Disease and Cancer in the Level of Genetics, Circulating Biomarkers, Microbiota and Environmental Risk Factors ( BIOMENDELIAN)

The problem being addressed in BIOMENDELIAN:

The purpose of this proposal is to provide novel understanding of causal connections between cardiometabolic traits and incidence of type 2 diabetes (T2D), cardiovascular disease (CVD) and cancer, and of interactions between genetic and dietary risk factors for cardiometabolic disease, and to clarify their connection to gut and oral microbiota and cancer. Investigating the complex interactions between dietary factors, genetic risk factors, circulating biomarkers and gut and oral microbiota constitution in a comprehensive prospective cohort study design is a crucial first step to allow for subsequent intervention studies. The purpose of this proposal is to provide novel intervention strategies aiming to more effective prevention of cardiometabolic disease and cancer.

Why is BIOMENDELIAN important for society?

The prevalence of obesity and type 2 diabetes increase severely in the World, including in European countries. Obesity and type 2 diabetes increase the risk for cardiometabolic complications such as coronary heart disease and stroke, and cardiovascular mortality, and obesity is also a risk factor for amny common cancer forms.
As these conditions severely decrease the quality of life of a person, but also severely increase the economical burden for the society (loss of working power and high medical costs), it is important to find novel effective ways to prevent obesity and the asociated diseases that increase the risk of mortality.

What are the overall objectives of BIOMENDELIAN?

1. To investigate causality between genetic risk factors for cardiometabolic traits and future incidence of type 2 diabetes (T2D), cardiovascular disease (CVD), cancer (total and subtypes of common forms) and mortality (total, CVD- and cancer mortality), searching for connecting and disconnecting causal factors
2. To investigate how gut and oral microbiome are regulated by dietary factors, gut satiety peptides and host genetics, and how such connections relate to the risk of cardiometabolic diseases and cancer, in a large population
3. To understand the role of diet and gene-diet interactions of importance for cardiometabolic disease and cancer aiming to better nutrition recommendations
4. To perform genotype, biomarker and gut microbiota based diet intervention studies. Individuals for lipid- and carbohydrate challenges and to longer diet interventions are selected based on extreme genotypes, gut hormone levels and gut microbiome.

Work performed

Please find the report of work performed during the first 18 months of BIOMENDELIAN, divided to four sections that correspond to the four objectives listed above:

TASK 1. Causality between genetic risk factors for cardiometabolic traits and future incidence of T2D, CVD, cancer and mortality: connecting and disconnecting causal factors.

1.1. Neurotensin work.
Neurotensin (NT), the ligand of neurotensin receptor-3, is a satiety hormone released from the small intestine and the CNS in response to in particular fatty meals. We have earlier found that high levels of a stable fragment of proneurotensin (PNT), predicts not only the development of CVD but also diabetes and breast cancer in healthy women (JAMA 2012, Orho-Melander last author). NT thus links cholesterol metabolism both with CMD and cancer, which is of particular interest as NT- system can potentially be modified by life-style and drugs. We have now shown (Publ 1 Li et al. Nature 2016) that NT-deficient mice demonstrate significantly reduced intestinal fat absorption and are protected from obesity, hepatic steatosis and insulin resistance associated with high fat consumption. In humans we show that both obese and insulin-resistant subjects have elevated plasma concentrations of pro-NT, and in longitudinal studies among non-obese subjects, high levels of pro-NT denote a doubling of the risk of developing obesity later in life. Our findings directly link NT with increased fat absorption and obesity and suggest that NT may provide a prognostic marker of future obesity and a potential target for prevention and treatment.

1.2. Novel biomarkers for kidney function.
We have investigated novel biomarkers for longitudinal deterioration of kidney function. We examined whether circulating proenkephalin (pro-ENK) levels predict chronic kidney disease (CKD) and decline of renal function in a prospective cohort of 2568 participants without CKD (eGFR>60 ml/min per 1.73 m2) at baseline. During a mean follow-up of 16.6 years, 31.7% of participants developed CKD. Participants with baseline pro-ENK levels in the highest tertile had significantly greater yearly mean decline of eGFR (Ptrend<0.001) and rise of cystatin C (Ptrend=0.01) and creatinine (Ptrend<0.001) levels (Publ 2 Schulz et al. JACN 2017). Furthermore, compared with participants in the lowest tertile, participants in the highest tertile of baseline pro-ENK concentration had increased CKD incidence (odds ratio, 1.51; 95% confidence interval, 1.18 to 1.94) when adjusted for multiple factors. Adding pro-ENK to a model of conventional risk factors in net reclassification improvement analysis resulted in reclassification of 14.14% of participants. Genome-wide association analysis in 4150 participants of the same cohort revealed the strongest association of pro-ENK levels with rs1012178 near the PENK gene, where the minor T-allele associated with a 0.057 pmol/L higher pro-ENK level per allele (P=4.67x10-21). Furthermore, the T-allele associated with a 19% increased risk of CKD per allele (P=0.03) and a significant decrease in the instrumental variable estimator for eGFR (P<0.01) in a Mendelian randomization analysis. In conclusion, circulating plasma pro-ENK level predicts incident CKD and may aid in identifying subjects in need of primary preventive regimens. Additionally, the Mendelian randomization analysis suggests a causal relationship between pro-ENK level and deterioration of kidney function over time.
As the soluble urokinase-type plasminogen activator receptor (suPAR) has recently been associated with a decline in kidney function and incidence of chronic kidney disease in patients with cardiovascular disease undergoing cardiac catheterization, we investigated whether suPAR is associated with deterioration of kidney function in the general population. In the Malmö Diet and Cancer Study cohort, participants within the highest quartile of suPAR had a significantly lower mean eGFR at follow-up than those within the lowes

Final results

This project will contribute to biological understanding of basic cardiovascular- and metabolic disease mechanisms. Without understanding how genetic and environmental risk factors interact to increase individual’s risk for cardiometabolic diseases, we have little use of neither the genetic nor the environmental risk factors in disease prevention and prediction of these diseases. Genetic and dietary risks for these disease traits are dependent on each other, and may also contribute to risk of cancer, and this project will provide novel information on how these risk factors interact. Understanding the complex interactions and their mechanisms challenged within the project will facilitate design of novel dietary or pharmacological intervention strategies that can favorably affect individual disease risk and lead to more effective, personalized, disease prevention.