Obesity, genetically elevated bilirubin and cancer risk

Obesity, usually marked by a high body mass index (BMI), is now an established risk factor for the development of many different cancers. However, not all obese individuals, even with the same body fat content and body fat distribution, develop these cancers. One likely explanation is that physiological characteristics of a person such as gender, age, or genetics together with having an elevated body fat content may render an individual more or less prone to develop cancer. One promising physiological characteristic in changing the effect of obesity on cancer is genet- ically elevated bilirubin. Bilirubin is an end product of the normal degradation process of red blood cells. It has long been thought that bilirubin possesses little or no physiological function, but scientific evidence has demonstrated that bilirubin actually exhibits substantial anti- inflammatory and antioxidant properties. Mildly elevated bilirubin levels with normal liver function tests are generally indicative of a condition described as Gilbert syndrome (GS), which is a common condition affecting 5-20% of the population (depending on ethnicity and gender). Individuals with GS usually have a favorable metabolic health such as improved glucose me- tabolism, lower BMI, lower body fat mass, and a more efficient energy metabolism. Further, individuals with GS appear to be at lower risk for developing chronic diseases including can- cer. Based on these existing data, it seems plausible that individuals with elevated bilirubin levels are less prone to develop cancers associated with obesity. Our main aim is to compare the risk of developing obesity-related cancers between obese individuals with and without mildly elevated bilirubin levels; we will also compare these risks to normal weight individuals with and without mildly elevated bilirubin levels. Our specific objectives are: 1. To investigate associations between obesity/bilirubin defined metabolic health types and the risk of developing obesity-related cancers combined and specifically cancers of the colorectum, breast, endometrium and pancreas; 2. To explore whether the favorable metabolic health of individuals with mildly elevated bilirubin levels can explain associations between obesity/bilirubin defined metabolic health types and the risk of developing obesity-related cancers combined and those of the colorectum, breast, endometrium and pancreas; 3. To explore whether individuals genetically pre-disposed to both obesity (=obese geno- type) and the Gilbert syndrome (=GS genotype) have a different risk of developing cancers of the colorectum, breast, endometrium and pancreas compared to individuals who have an obese genotype, but not a GS genotype. These studies with large international data sets will help to understand the potential of the hy- perbilirubinaemic genotype to protect from obesity related cancers.

Obesity, usually marked by a high body mass index (BMI), is now an established risk factor for the development of many different cancers as well as cardiometabolic diseases. However, not all obese individuals, even with the same body fat content and body fat distribution, develop these cancers. One likely explanation is that physiological characteristics of a person such as gender, age, or genetics together with having an elevated body fat content may render an individual more or less prone to develop cancer. One promising physiological characteristic in changing the effect of obesity on cancer is genet-ically elevated bilirubin. Bilirubin is an end product of the normal degradation process of red blood cells. It has long been thought that bilirubin possesses little or no physiological function, but scientific evidence has demonstrated that bilirubin actually exhibits substantial anti-inflammatory and antioxidant properties. Mildly elevated bilirubin levels - with normal liver function tests - are generally indicative of a condition described as Gilbert syndrome (GS), which is a common condition affecting 5-20% of the population (depending on ethnicity and gender). The present project investigated the links between obesity/bilirubin defined metabolic health types and the risk of developing obesity-related cancers combined and with focus on cancers of the colorectum, breast, endometrium and pancreas and tried to explore whether a favorable metabolic health of individuals with mildly elevated bilirubin levels can explain associations between obesity/bilirubin defined metabolic health types and the risk of developing obesity-related cancers and other metabolic diseases. Data from several large international studies (EPIC: European Prospective Investigation into Cancer and Nutrition; UK Biobank, KoGES_HEXA from South Korea and the Genetic consortia on cancers of the colorectum, breast, pancreas, and endometrium) were analyzed. We were also able to address the question in the European MARK-AGE study. Data from the UK Biobank, taking into account 467,519 participants, show very interesting correlations. Higher bilirubin levels were negatively associated with indicators of overall adiposity (BMI and fat mass) as well as body fat distribution in the trunk in both men and women. Therefore, we could conclude that higher bilirubin levels are inversely associated with cardiometabolic risk factors such as obesity, dyslipidemia or hypertension. Very similar results were found in the MARK-Age study, where older people with slightly elevated bilirubin levels had a much lower concentration of cardiometabolic risk factors in their blood (e.g. lower BMI, HbA1c, insulin, triglycerides, total cholesterol, LDL cholesterol, fewer points in the Framingham risk score or higher HDL cholesterol) than those with low bilirubin levels in their blood. Further evaluations, particularly regarding cancer risk are ongoing or are at the moment with promising results in papers which are submitted.