1. Iron, Cholesterol, and Cancer Brian J. Wells, MD, MS The Cleveland Clinic Foundation

2. Thanks!!!!! MUSC –Dr. Mainous –Dr. Everett Christiana Care Health System –Dr. Gill

3. Reactive Oxygen Species (ROS) Dietary Imbalance Chronic Infections/ Inflammation Impaired Metal transport (↑ Iron) Lipid Peroxidation DNA DAMAGE Signal Transduction Cell Proliferation Apoptosis Chronic Degenerative Diseases

4. Reactive Oxygen Species (ROS) “Oxidative Stress” Lipid Peroxidation DNA DAMAGE Iron + LDL Neoplasia

5. Epi Studies Elevated TS (>55%) and LDL (> 160mg/dl) increase risk of CHD mortality and all-cause mortality Elevated TS (>37%) and TC (268mg/dl) increase risk of AD Elevated Ferritin (>200ng/ml) and LDL (>160mg/dl) associated with increased insulin resistance Elevated Ferritin (>200ng/ml) and LDL (>160mg/dl) associated with elevated CRP

6. NHANES I (1971-1974) multistage, stratified, probability, cluster sampling of non-institutionalized persons 1–74 years of age Oversampling of population subgroups –Elderly –Women of childbearing age –Persons living in poverty areas >14,000 participants

7. NHEFS Longitudinal Assessment of Morbidity and Mortality (1982-1984, 1986, 1987 and 1992) –Contact and interview Participant –Contact and interview Proxy –Death Certificate Data >98% of NHANES I participants tracked in 1992

8. Inclusion Criteria –Individuals > 25 y.o. at NHANES I baseline with serum Iron and Total Cholesterol levels Exclusion Criteria –Individuals with physician diagnosed tumors (other than non-melanoma skin cancer) Un-weighted N = 7,448

9. Independent and Dependent Variables Total Cholesterol –Dichotomized at 75 th percentile (248.08mg/dl) Serum Iron –Dichotomized at 75 th percentile (122.44μg/dl) Cancers –ICD 9 codes 140-239 –Excluding non-melanoma skin cancer (173.xx)

10. Control Variables AgeGenderRaceSmoking Body Mass Index Comorbid Cancer Risk Factors –Chronic hepatitis, Chronic colitis Symptoms of undiagnosed cancer at baseline –Chronic cough, melana/hematochezia

11. Analysis Population stratified into 4 groups based on iron and lipid levels. Sampling weights used to create prevalence estimates for US population Analysis Conducted using SUDAAN as recommended by NCHC Cox Proportional Hazard models of time to Cancer in each group with controls

14. Adjusted Cox Proportional Hazard Models (Elevated defined as >75th percentile) Hazard Ratio Confidence Interval Elevated Serum Iron (>122  g/dl) 1.170.97-1.41 Elevated Cholesterol (>248 mg/dl) 1.110.89-1.38 Elevated Serum Iron and Elevated Cholesterol 1.391.00-1.94 Adjusted for age, sex, race, smoking status, BMI, chronic cough, chronic hepatitis, chronic/recurrent colitis or enteritis, and gastrointestinal bleeding.

15. * * * P<0.05 Adjusted for age, sex, race, smoking status, BMI, chronic cough, chronic hepatitis, chronic/recurrent colitis or enteritis, and gastrointestinal bleeding.

16. Conclusions Results support the Iron, Lipid, and oxidative stress hypothesis. Exciting possibilities for cancer chemo- prevention Results should not be interpreted to change clinical practice No proof of biological mechanism Need intervention studies.

17. Weaknesses One time measurements of cholesterol and Iron Iron and cholesterol are “crude” markers Classification bias (death certificate data) Undiagnosed cancer at baseline

18. Strengths Cohort Rigorous methodology Controls Large sample size Generalizability

20. Prostate Cancer Strong evidence supporting a role of Oxidative Stress Men –Higher Iron –Dyslipidemia Possible link with Heart Disease Recent studies suggest decreased risk for statin users.

21. Ongoing/future Research Histological Examination of OS in Prostate Cancer Case Control Study of Iron, Lipids, and OS in prostate Cancer MUSC – Cross section study of Iron, lipids and oxidative stress Interventional study of Statins in early prostate cancer Statin chemoprevention Trial

22. The End