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


Project ID: 649021
Funded under: H2020-EU.1.1.

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

Reporting period: 2015-09-01 to 2017-02-28

Summary of the context and overall objectives of the project

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 from the beginning of the project to the end of the period covered by the report and main results achieved so far

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 lowest quartile (mean 68 vs. 74 ml/min per 1.73 m2; P-trend = 4.3 × 10-7) (Publ 3. Schulz et al. KIR 2017). In multivariate regression analysis, suPAR (per 1 SD increment of log-transformed suPAR) was associated with a decline in eGFR (P = 3.3 × 10-9) and incident chronic kidney disease (561 events, odds ratio = 1.25; 95% confidence interval, 1.10-1.41). Furthermore, we identified 110 cases of hospitalization due to impaired kidney function via linkage to national registers of inpatient and outpatient hospital diagnoses. During a mean follow-up time of 19 years, suPAR was associated with risk for hospitalization due to impaired kidney function (hazard ratio = 1.49; 95% confidence interval, 1.27-1.74) in multivariate Cox proportional hazard analysis.The increased suPAR level at baseline was associated with a significantly higher longitudinal decline in eGFR, higher incidence of chronic kidney disease, and hospitalization due to impaired kidney function in a cohort of healthy middle-aged participants.

1.3. Connection between cardiometabolic disease and cancer.
Earlier studies have indicated that type 2 diabetes (T2D) and adiposity associate with increased risk of several cancers, but the impact of competing risk of non-cancer deaths on these associations is not known. We therefore prospectively examined participants in the Malmö Diet and Cancer Study aged 44-73 years with no history of cancer at baseline (n=26,953, 43% men). T2D was ascertained at baseline and during follow-up, and body mass index (BMI) and waist circumference (WC) at baseline. Multivariable cause-specific hazard ratios (HR) and sub-distribution hazard ratios (sHR), taking into account non-cancer deaths, were estimated using Cox- and competing risk regression. During follow-up (mean 17 years), 7,061 incident cancers (3,220 obesity-related cancer types) and 2,848 cancer deaths occurred. BMI and WC were associated with increased risk of obesity-related cancer incidence and cancer mortality. In T2D subjects, risk of obesity-related cancer was elevated among men (HR=1.31, 95% CI: 1.12-1.54; sHR=1.29, 95% CI: 1.10-1.52), and cancer mortality among both men and women (HR=1.34, 95% CI: 1.20-1.49; sHR=1.30, 95% CI: 1.16-1.45) (Publ 4. Drake at al. Int J Epidem, revised version under review 2017). There was no elevated actual risk of cancer death in T2D patients with long disease duration (sHR=1.00, 95% CI: 0.83-1.20). Comorbid T2D and adiposity was associated with a marked increased risk of obesity-related cancer and cancer mortality. In conclusion, detection bias may partially explain the increased risk of cancer morbidity among T2D patients. Both excess risk of competing events among patients with T2D and depletion of susceptibles due to earlier cancer detection will lower the actual risk of cancer, particularly with longer diabetes duration and at older ages.

We have also by using Mendelian Randomization approach found evidence for causal, inverse association between serum triglycerides and overall cancer risk. Further, the LDLC-lowering effect of statins may increase prostate cancer risk (Publ 5. Orho-Melander et al. 2017). These novel results require replication in other studies.
In addition to these already finished studies, we have three BIOMENDELIAN manuscripts under preparation as result of our research under “Aim 1” of the project (PUBL 6-8, see below).

Publications and submitted manuscripts TASK1/AIM1:
1. Li J, Song J, Zaytseva YY, Liu Y, Rychahou P, Jiang K, Starr ME, Kim JT, Harris JW, Yiannikouris FB, Katz WS, Nilsson PM, Orho-Melander M, Chen J, Zhu H, Fahrenholz T, Higashi RM, Gao T, Morris AJ, Cassis LA, Fan TW, Weiss HL, Dobner PR, Melander O, Jia J, Evers BM. An obligatory role for neurotensin in high-fat-diet-induced obesity. Nature. 2016 May 11;533(7603):411-5.
2. Schulz CA, Christensson A, Ericson U, Almgren P, Hindy G, Nilsson PM, Struck J, Bergmann A, Melander O, Orho-Melander M. High Level of Fasting Plasma Proenkephalin-A Predicts Deterioration of Kidney Function and Incidence of CKD. J Am Soc Nephrol. 2017 Jan;28(1):291-303.
3. Schulz CA, Persson M, Christensson A, Hindy G, Almgren P, Nilsson PM, Melander O, Engström G, Orho-Melander M: Soluble Urokinase-type Plasminogen Activator Receptor (suPAR) and Impaired Kidney Function in the Population-based Malmö Diet and Cancer Study. Kidney Int Rep. 2017 Mar;2(2):239-247. doi: 10.1016/j.ekir.2016.11.004.
4. Drake DI, Gullberg B, Sonestedt E, Stocks T, Bjartell A, Wirfält E, Wallström P, Orho-Melander M: Type 2 diabetes, adiposity, and cancer morbidity and mortality risk taking into account competing risk of non-cancer deaths in a prospective cohort setting. Int J Epidem 2017 revised version under review 2017
5. Orho-Melander M, Hindy G, Borgquist S, Schulz C-A, Manjer J, Melander O, Stocks T: Blood lipid genetic scores, the HMGCR gene, and cancer risk: a Mendelian Randomization study, submitted 2017
6. Schulz C-A, Engström G, Nilsson J, Nilsson PM, Melander O, Orho-Melander M:
High levels of plasma T-cell immunoglobulin and mucin-containing molecule 1 (TIM-1) predict deterioration of kidney function and incidence of chronic kidney disease. Manuscript in preparation 2017
7. Hindy G, Rukh G, Almgren P, Schulz CA, Ericson U, Fava C, Engström G, Melander O, Orho-Melander M: Causal role of common cardio-metabolic traits in type 2 diabetes and coronary heart disease: a Mendelian randomisation study. Manuscript in preparation 2017
8. Hindy G, Almgren P, Melander O, Orho-Melander M: Role of Genetically Determined Levels of Lipid Fractions in the Development of Ischemic Stroke and Subtypes, Manuscript in preparation 2017

TASK 2. Gut and oral microbiome in a large population: regulation by dietary factors, gut satiety peptides and host genetics: relation to the risk of cardiometabolic diseases and cancer

Malmö Offspring Study (MOS) is an inter-generational study where all adult children and grand-children to individuals in the population-based Malmö Diet and Cancer - Cardiovascular cohort (MDC-CV, N=6103) are invited to participate. All available offspring (around 15 000) and a number of spouses to individuals in the MDC-CV study cohort are invited to participate and the goal is to collect data on 6000 individuals. Subjects are invited to examinations at the Clinical Research Unit, Skåne University Hospital, Malmö. Within Biomendelian, we collect dietary data and faecal samples for microbiota sequencing. Malmö Offspring Dental Study, MODS, is an oral health and oral microbiome study arm of MOS, and the oral microbiome part of MODS is a close collaboration with Malmö Dental High School (Daniel Jönsson, PhD, Dentist).

The MOS study cohort is unique with detailed phenotype information including parental and grandparental disease history, and GWAS genotyping of the parents and grandparents. It is also unique with detailed information on dietary habits and collection of feces and oral samples. MODS follows the same study strategy as MOS with a pilot study of 500 subjects, and a plan for expansion to cover the whole MOS cohort.
Dietary intakes are recorded via the internet during 4 days with the method used in the latest national diet survey (“Riksmaten 2010-2011”) from the Swedish National Food Administration. The diet assessment material includes (i) a food diary, (ii) a portion guide for estimation of portion sizes showing pictures of 24 different food categories (with four to eight different reference sizes for each category), and (iii) an information folder, “How to keep food records”. The participants are asked to keep their normal dietary habits during these days. To assure high compliance and high quality dietary data, the participants receive a telephone call from a nutritionist on the second day of their record period. In addition to the diet record a short food propensity questionnaire is used, in order to obtain information about usual intakes of key foods earlier identified to be consumed irregularly or seldom (e.g. different types of vegetables and fish).

Update of the project status by April 25th 2017:
We have now collected more than 2500 samples within MOS and around 1000 of them have participated in MODS. 87% of the individuals have provided feacal samples and 68% dietary data. Of the collected 2175 faecal samples, 930 have been sequenced so far, and the remaining 1245 samples are under sequencing. Unfortunately we had a delay in this project during 2016 as we had technical problems with the DNA extraction and sequencing. This caused us around 4-5 months delay in the project and this is also the reason why we have not yet used all the budgeted grant money. We have now solved the issue, and are catching up the time we lost. After summer 2017 we expect to be in balance with both our time plan and budget in the project, and we will be ready with 2500 samples feacal sequencing analyses.

We still are in the middle of analyszing the data as well as collecting more samples, and therefore we do not yet have published data. However, within the project, we have written a review to Diabetologia about the role of gut microbiota in type 2 diabetes (Publ 9. Brunkwall & Orho-Melander 2017).

Publications and submitted manuscripts TAS2/AIM2:
9. Brunkwall L, Orho-Melander M: The gut microbiome as a target for prevention and treatment of hyperglycaemia in type 2 diabetes: from current human evidence to future possibilities. Diabetologia. 2017 Apr 22. doi: 10.1007/s00125-017-4278-3. [Epub ahead of print] Review.

TASK 3. Role of diet and gene-diet interactions of importance for cardiometabolic disease and cancer aiming to better nutrition recommendations

AMY1, starch intake and obesity.
We investigated the association between AMY1 copy number and obesity traits and the interaction between AMY1 copy number and starch intake on these obesity traits. AMY1 copy number was not associated with BMI (P=0.80) or body fat percentage (P=0.38). We observed a significant interaction between AMY1 copy number and starch intake on BMI (Pinteraction=0.007) and body fat percentage (Pinteraction=0.03) (Publ 10. Rukh et al. Am J Clin Nutr 2017, in press). Upon stratification by dietary starch intake, BMI tended to decrease with increasing AMY1 copy numbers in the low starch intake group (P=0.07) and tended to increase with increasing AMY1 copy numbers in the high starch intake group (P=0.08). The lowest average BMI was observed in the group of participants with a low AMY1 copy number and a high dietary intake of starch. Our findings suggest an interaction between starch intake and AMY1 copy number on obesity. Individuals with high starch intake but low genetic capacity to digest starch had the lowest BMI, potentially because larger amounts of undigested starch are transported through the GI tract, contributing to fewer extracted calories from ingested starch.

Dietary patterns and cardio-metabolic health.
In this study we derived dietary patterns that explain variation in cardio-metabolic traits and examined their association with prospective change in cardio-metabolic traits and incident metabolic syndrome (iMetS). Subjects from the Malmö Diet and Cancer Study free of cardio-metabolic disease and related drug treatments at baseline, and with fasting blood samples (N=4,071; aged 45-67 y, 40% men) were included. We applied reduced rank regression on 38 foods to derive patterns that explain variation in response variables measured at baseline 1991-1994 (waist circumference, triglycerides, HDL- and LDL-cholesterol, systolic and diastolic blood pressure, fasting glucose and insulin). Patterns were examined in relation to change in cardio-metabolic traits and iMetS (defined by the National Cholesterol Education Program – Adult Treatment Panel III) in subjects that were re-examined after 16 y (N=2,704). Two dietary patterns (“Western” and “Drinker”) were retained and explained 3.2% of the variation in response variab
les. The “Western” dietary pattern was inversely associated with HDL cholesterol and positively associated with all other response variables (both at baseline and follow-up), the only exception being lack of association with LDL at follow-up. The multivariable odds ratio for iMetS in the highest quartile compared to the lowest of the “Western” dietary pattern score was 1.68 (95% CI: 1.31-2.16; P-trend<0.0001) (Publ 11. Drake et al. under review 2017). The “Drinker” pattern added mostly to explaining variation in HDL but was not associated with iMetS. Our study supports evidence suggesting that a “Western” dietary pattern with high intakes of sugar-sweetened beverages, red and processed meats and low intakes of wine, cheese, vegetables, and high-fiber foods is associated with detrimental effects on several cardio-metabolic risk factors. However, the explained variation in selected traits was modest.

In addition to these already finished studies, we have two other BIOMENDELIAN manuscripts under preparation as result of our research under “Aim 3” of the project (PUBL 12-13, see below).

Publications and submitted manuscripts TAS3/AIM3:
10. Rukh G, Ericson U, Andersson-Assarsson J, Orho-Melander M, Sonestedt E: Dietary starch intake modifies the relationship between copy number variation in the salivary amylase gene and BMI. Am J Clin Nutr 2017, in press
11. Drake I, Sonestedt E, Ericson U, Wallström P, Orho-Melander M: Dietary patterns, cardio-metabolic traits, and incidence of metabolic syndrome: A Prospective study in the Malmö Diet and Cancer cohort Am J Clin Nutr 2017, revised version under review
12. Hindy G, Wiberg F, Almgren P, Melander O, Orho-Melander M: A Polygenic Risk Score for Coronary Heart Disease Modifies the Elevated Risk by Cigarette Smoking for Disease Incidence, submitted 2017
13. Ericson U, Hindy G, Drake I, Schulz C-A, Brunkwall L, Hellstrand S, Almgren P and Orho-Melander M: Dietary and genetic risk factors for type 2 diabetes increase the risk in an independent fashion, submitted 2017

TASK 4. Genotype, biomarker and gut microbiota based diet intervention studies.
This part of the project has not been initiated yet. Planned to be initiated in 2018.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

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.
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