Nutzung von Biomarkern in großen epidemiologischen Studien

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1 Deutsches Institut für Ernährungsforschung Potsdam-Rehbrücke Nutzung von Biomarkern in großen epidemiologischen Studien Priv.-Doz. Dr. med. Tobias Pischon, MPH Leiter, Arbeitsgruppe Biomarker Abteilung Epidemiologie

2 Deutsches Institut für Ernährungsforschung Potsdam-Rehbrücke Forschungsschwerpunkte Metabolisches Syndrom Ernährung und Krebserkrankungen Institut der Wissenschaftsgemeinschaft Gottfried Wilhelm Leibnitz

3 Epidemiologie Definition Epidemiologie: Die Untersuchung der Verbreitung und der Determinanten von gesundheitsbezogenen Zuständen und Ereignissen (Krankheiten) in menschlichen Populationen (Lilienfeld, 1976) Definition Ernährungsepidemiologie: Untersuchung der Beziehung von Ernährungsfaktoren mit dem Auftreten von Erkrankungen in menschlichen Populationen

4 Use of Biomarkers in Epidemiology Modification of risk and Evaluation of success of intervention Biomarker Identification of individuals at risk for disease (before disease develops) Internal dose Exposition Public health level Biologically effective dose Early biological effects Structural/ functional alterations Disease Biologic-mechanistic level Susceptibility modified from Chen et al., CA Cancer J Clin 2005;55(1):45-54 and Hoffmann et al., Gesundheitswesen 2002;64(2):

5 European Prospective Investigation into Cancer and Land Nutrition Männer (EPIC) Frauen Dänemark Kohortenstudie Deutschland 23 Zentren Heidelberg in Ländern Potsdam Europas Rekrutierung Frankreich Griechenland Studienteilnehmer Großbritannien Alter Italien25-70 Jahre Niederlande Welche Nahrungsfaktoren Norwegen sind mit der Entstehung von Krebs Schweden und anderen chronischen Erkrankungen Spanien assoziiert? Gesamt OVIEDO CAMBRIDGE OXFORD SAN SEBASTIAN PAMPLONA AARHUS PARIS I.A.R.C UTRECHT BILTHOVEN LYON TROMSO BARCELONA MALMO COPENHAGEN POTSDAM HEIDELBERG UMEA MILAN TURIN FLORENCE NAPLES Gesamt ATHENS MURCIA GRANADA RAGUSA

6 Portionsgröße Verzehrshäufigkeit

7 Körpermaße, Blutentnahme

8 EPIC-Proben Tiefkühllagerung Preparation of of 28 aliquotes of of 450 µl µl :: Plasma Serum 8 buffy coat 4 red blood cells 4 Total: 28 x subjects = Million aliquots

9 Design der Langzeitstudie Mit Merkmal (Exponierte) Erkrankungsrisiko Studienpopulation Vergleich (relatives Risiko) Ohne Merkmal (Nicht-Exponierte) Erkrankungsrisiko Basisuntersuchung Nachbeobachtung 2. Nachbeobachtung 3. Nachbeobachtung 4. Nachbeobachtung Beginn der Studie

10 Energiebilanz und chronische Erkrankungen Adipositas Allgemeine A. Abdominale A. Typ-2-Diabetes Herz-Kreislauf-Erkrankungen Krebserkrankungen Mortalität Berrington de Gonzalez et al. Cancer Epidemiol Biomarkers Prev 2006 Friedenreich et al. Cancer Causes Control 2007 Heidemann et al. Eur J Cardiovasc Prev Rehabil 2007 Lahmann et al. Int J Cancer 2004 Pischon et al. Int J Cancer 2006 Pischon et al. J Natl Cancer Inst 2006 Pischon et al. Proc Nutr Soc 2008 Pischon et al. Cancer Epidemiol Biomarkers Prev 2008 Pischon et al. N Engl J Med 2008 Schulze et al. Diabetes Care 2006

Obesity Related Biomarkers Weight gain lean adipose

Macrophage apoptotischer Adipozyt Adipocytokines

necrosis factor Interleukin-6 Chemokine (C-C motif)

11 Obesity Related Biomarkers Weight gain lean adipose tissue obese adipose tissue Adipocyte blood vessel Macrophage apoptotischer Adipozyt Adipocytokines Adiponectin Leptin Macrophage derived factors Interleukin-1β Resistin (humans) Liver Pro-inflammatory cytokines und chemokines Tumor necrosis factor Interleukin-6 Chemokine (C-C motif) ligand 2 Akute-phase-proteins C-reaktive protein (CRP) Tilg & Moschen, Nat Rev Immunol 2006 (modified)

12 Resistin 114-amino acid polypeptide (12.5 kda) hormone Family of resistin-like molecules Animal models - Secreted by adipocytes, causing insulin resistance - Positive association with insulin resistance or obesity - Link between obesity and type 2 diabetes? Humans - Resistin structure differs substantially between species - No clear association with obesity or type 2 diabetes - Expressed predominantly in circulating blood monocytes - Activates human endothelial cells, leading to increased expression of adhesion molecules, and induced human aortic muscle cell proliferation - Involved in inflammation, link to CVD? Steppan et al., Nature 2001 Steppan et al., Proc Natl Acad Sci U S A 2001 Holcomb, Embo J 2000

13 Incident CVD in EPIC-Potsdam 26,490 participants without CVD Average follow-up: 6 years 156 cases of myocardial infarction (MI) 103 cases of ischemic stroke (IS) Baseline 1. Follow-up 2. Follow-up 3. Follow-up 4. Follow-up Case cohort design 156 cases of incident MI Subcohort 850 participants 103 cases of incident IS Cohort 26,490 participants

14 Plasma Resistin Levels and Risk of CVD (EPIC-Potsdam, 6.0 Years of Follow-up) Myocardial infarction Resistin quartile P trend Relative risk (95%-CI) MV-adjusted ( ) 2.1 ( ) 2.4 ( ) Ischemic stroke + CRP ( ) 2.1 ( ) 2.1 ( ) 0.01 MV-adjusted ( ) 1.1 ( ) 1.1 ( ) CRP ( ) 1.1 ( ) 0.9 ( ) 0.9 Multivariable adjustment includes age, sex, smoking, education, BMI, waist circumference, physical activity, alcohol consumption, hypertension, diabetes, total cholesterol, and HDLcholesterol Weikert, Pischon; J Clin Endocrinol Metab 2008

15 Adiponectin CHD Obesity Biomarkers and Incident Cardiovascular Disease Pischon et al. Jama 2004 Inflammatory markers CRP CHD IL-6, stnf-r1/-r2 Pai, Pischon et al. N Engl J Med 2004 (joint first authorship) Pischon et al. Eur J Epidemiol 2007 Resistin CHD Pischon et al. Obes Res 2005 Weikert,... Pischon, J Clin Endocrinol Metab 2008 Fetuin CHD, stroke Weikert et al. Circulation 2008

16 Association of FTO rs With Plasma CRP Levels (EPIC-Potsdam) FTO rs TT TA AA Per A-Allele P Partial R 2 CRP levels, men, mg/l age adjusted % multivariable adjusted* % CRP levels, women, mg/l age adjusted % multivariable adjusted* % *adjusted for age, BMI, WHR, history of MI, history of stroke, history of diabetes, education, physical activity, and smoking status Fisher,, Pischon, Obesity (Silver Spring) 2009

17 Reliability of Biomarker Levels Over Time Biomarker Time interval Intraclass correlation coefficient σ b 2 (σ b 2 +σ w 2 ) stnf-r1 4 years 0.81 stnf-r2 4 years 0.78 IL-6 4 years 0.47 CRP 4 years 0.67 Adiponectin 1 year 0.85 Resistin 1 year 0.70 Pischon et al.; Circulation 2003 Pischon et al.; Clin Chem 2003 Weikert,, Pischon; Clin Chem Lab Med 2007

18 Stability of Adiponectin in Blood Samples Processed 0, 24, and 36 Hours After Blood Collection Adipnectin (mg/l) Time EDTA (n=12) P* Heparin (n=12) P* 0 Hours Hours Hours Intraclass correlation *Compared with adiponectin levels at 0 hours (paired t-test of geometric means) Pischon et al., Clin Chem 2003; 49:650

19 The Value of Blood Samples Stored blood samples in cohort studies are usually a limited resource The longer the follow-up, the higher the value of the cohort study, and, consequently, the higher the value of the biomarkers Analysis of biomarkers is usually expensive (estimate: Euros per sample for novel plasma markers)

20 Efficient Use of Blood Samples Adequately address the study question / hypothesis with the smallest amount of blood necessary and without affecting any remaining specimen Adequately address the study question / hypothesis with the smallest amount of money

21 Lobaratory Analysis of Biomarkers Usually not only one but several biomarkers E.g. in CVD it is usually necessary also to analyze TC, LDL-C, HDL-C, TG Each biomarkers requires a sampling volume (for analysis) and usually a residual volume (for technical reasons) Volume needed per biomarker may vary (e.g., 50 to 200 µl per biomarker)

22 Issues to Consider for Use of Biomarkers High sensitivity and specificity High validity (assay should measure what it is intended to measure) High accuracy and precision High degree of standardization Methods should be easy to use High stability Biomarker should usually have high reliability (i.e., reflect longterm exposure) Low sample volume Low price

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