Biologische Marker in der Epidemiologie:   Begriffe, Anwendungen, Perspektiven (Teil II)

W. Hoffmann; U. Latza; W. Ahrens; K. H. Greiser; A. Kroke; A. Nieters; M. B. Schulze; M. Steiner; C. Terschüren; M. Wjst

doi:10.1055/s-2002-22313

Gesundheitswesen 2002; 64(3): 145-152
DOI: 10.1055/s-2002-22313

Originalarbeiten

Biologische Marker in der Epidemiologie: Begriffe, Anwendungen, Perspektiven (Teil II)

Biological Markers in Epidemiology: Concepts, applications, Perspectives (Part II)W. Hoffmann, U. Latza, W. Ahrens, K. H. Greiser, A. Kroke, A. Nieters, M. B. Schulze, M. Steiner, C. Terschüren, M. Wjst

¹Die Autoren stehen für die gemeinsame Arbeitsgruppe „Epidemiologische Methoden” der Deutschen Arbeitsgemeinschaft Epidemiologie (DAE), der Deutschen Gesellschaft für Sozialmedizin und Prävention (DGSMP) und der Deutschen Gesellschaft für Medizinische Statistik, Biometrie und Epidemiologie (GMDS)

Abstract

Zusammenfassung

Im ersten Teil dieses Hintergrundpapiers wurden Begriffe im Kontext der Anwendung von biologischen Markern in epidemiologischen Studien definiert und deren historische Entwicklung am Beispiel der Herz-Kreislauf-Epidemiologie dargestellt. Im Zentrum des zweiten Teils stehen DNA-basierte Biomarker, praktische und methodische Aspekte des Einsatzes von Biomarkern in analytischen epidemiologischen Studien sowie Anforderungen an deren Validierung und Qualitätssicherung. Polymorphismen in der DNA besitzen vermutlich keinen eigenständigen Krankheitswert. Einige können jedoch als Marker zum Nachweis von individueller Sensitivität gegenüber Expositionen und Suszeptibilität für bestimmte Erkrankungen in epidemiologischen Studien eingesetzt werden. Das Human-Genom-Projekt hat zu einem Quantensprung der Möglichkeiten für die Entwicklung von genetischen Markern geführt, deren praktische Bedeutung gegenwärtig noch nicht vollständig ermessen werden kann. Forschungsprogramme zur Untersuchung von Gen-Umwelt-Interaktionen werden jedoch auch zukünftig auf die „traditionellen” epidemiologischen Designs, Methoden und Konzepte angewiesen sein. Berücksichtigung ethischer Prinzipien sowie Anforderungen des Datenschutzes und der „Guten epidemiologischen Praxis” gelten uneingeschränkt auch für die Genetische und Molekulare Epidemiologie.

Abstract

The first part of this paper outlined terms and definitions in the context of the application of biological markers in epidemiological studies. Cardiovascular epidemiology served as an example for their historical development. The second part focusses on DNA-based biomarkers, practical and methodological dimensions of the use of biomarkers in analytic epidemiological studies as well as requirements in respect of validity and quality assurance. Most genetic polymorphisms have no impact on health. However, some can be used as biomarkers for individual sensitvity to exposures and susceptibility for specific diseases. The Human Genome Project has brought about a quantum leap in the development of genetic markers. The practical implications cannot presently be assessed with certainty. However, present and future research programmes of gene-environment interactions depend on „traditional” epidemiological study designs, methods, and concepts. Ethical principles and data protection requirements apply equally to genetic and molecular epidemiology as do the „Guidelines for Good Epidemiological Practice”.

Schlüsselwörter

Biomarker - individuelle Suszeptibilität - individuelle Sensitivität - Molekulare Epidemiologie - SNP - Genetische Polymorphismen - Validität

Keywords

Biomarker - Individual susceptibility - Individual sensitivity - Molecular epidemiology - SNP - Genetic polymorphism - Validity

Full Text

References

Literatur

1 Gotoff S P, Amirmokri E, Liebner E J. Ataxia teleangiectasia Neoplasia, untoward response to x-irradiation, and tuberous sklerosis. American Journal of Diseases of Children. 1967; 114 617-625
2 Swift M, Chase C. Cancer in families with xeroderma pigmentosum. JNCI. 1979; 62 1415-1421
3 Parshad R, Sanford K K, Jones G M. Chromatid damage after G2 phase x-irradiation of cells from cancer-prone individuals implicates deficiency in DNA repair. Proceedings of the National Academy of Sciences. 1983; 80 5612-5616
4 German J, Crippa L P, Bloom D. Bloom’s syndrome. III. Analysis of the chromosome aberration characteristic of this disorder. Chromosoma. 1974; 48 361-366
5 Bigelow S B, Rary J M, Bender M A. G2 chromosomal radiosensitivity in Fanconi’s anemia. Mutat Res. 1979; 63 189-199
6 Wang S M, Nishigori C, Yagi T, Takebe H. Reduced DNA repair in progeria cells and effects of gamma-ray irradiation on UV-induced unscheduled DNA synthesis in normal and progeria cells. Mutat Res. 1991; 256 59-66
7 Weichselbaum R R, Nove J, Little J B. X-Ray Sensitivity of Fifty-three Human Diploid Fibroblast Cell Strains from Patients with Characterized Genetic Disorders. Cancer Res. 1980; 40 920-925
8 Weemaes C MR, Hustinx T WJ, Scheres J MJC, van Munster P JJ, Bakkeren J AJM, Taalman R DFM. A new chromosomal instability disorder: The Nijmegen Breakage Syndrome. Acta Paediat Scand. 1981; 70 557-564
9 Swift M, Reitnauer P J, Morrell D, Chase C L. Breast and other cancers in families with ataxia teleangiectasia. N Engl J Med. 1987; 316 1289-1294
10 Djuzenova C S, Schindler D, Stopper H, Hoehn H, Flentje M, Oppitz U. Identification of ataxia telangiectasia heterozygotes, a cancer-prone population, using the single-cell gel electrophoresis (Comet) assay. Lab Invest. 1999; 79 699-705
11 Swift M, Morrell D, Cromartie E, Chamberlin A R, Skolnick M H, Bishop D T. The Incidence and Gene Frequency of Ataxia-Telangiectasia in the United States. Am J Hum Genet. 1986; 39 573-583
12 Au W W, Oberheitmann B, Heo M Y, Hoffmann W, Oh H Y. Biomarker monitoring for health risk based on sensitivity to environmental mutagens. Reviews on Environmental Health. 2001; 16 41-64
13 Oberheitmann B, Schäfer J, Dally H, Garms A, Frentzel-Beyme R, Hoffmann W. The chromosome-based challenge assay using fluorescence in situ hybridization: a possible test for increased cancer susceptibility. Mutat Res. 1999; 428 157-164
14 Metabolic polymorphisms and susceptibility to cancer. Vineis P, Malats N, Lang M, d’Errico A, Caporaso N, Cuzick J, Bofetta P IARC Scientific Publication No. 148 Lyon; World Health Organisation 1999
15 Nakachi K, Imai K, Hayashi S -I, Kawajiri K. Polymorphisms of the CYP1A1 and Glutathione S-Transferase genes associated with susceptibility to lung cancer in relation to cigarette dose in a Japanese population. Cancer Res. 1993; 53 2994-2999
16 Yu M C, Skipper P L, Taghizadeh K, Tannenbaum S R, Chan K K, Henderson B E, Ross R K. Acetylator phenotype, aminobiphenyl-hemoglobin adduct levels, and bladder cancer risk in white, black, and Asian men in Los Angeles, California. JNCI. 1994; 86 712-716
17 Brockmoller J, Kerb R, Drakoulis N, Staffeldt B, Roots I. Glutathione S-transferase M1 and its variants A and B as host factors of bladder cancer susceptibility: a case-control study. Cancer Res. 1994; 54 4103-4111
18 Ketterer B, Harris J M, Talaska G, Meyer D J, Pemble S E, Taylor J B, Lang N P, Kadlubar F F. The human glutathione S-transferase supergene family, its polymorphism, and its effects on susceptibility to lung cancer. Environ Health Perspect. 1992; 98 87-94
19 Vineis P. Use of biomarkers in epidemiology. The example of metabolic susceptibility to cancer. Toxicology Letters. 1995; 77 163-168
20 Vineis P, Schulte P A. Scientific and ethical aspects of genetic screening of workers for cancer risk: the case of the N-acetyltransferase phenotype. J Clin Epidemiol. 1995; 48 189-197
21 Heckbert S R, Weiss N S, Hornung S K, Eaton D L, Motulsky A G. Glutathion S-Transferase and epoxide hydrolase activity in human leukocytes in relation to risk of lung cancer and other smoking-related cancers. JNCI. 1992; 84 414-422
22 Seidegård J, Pero R W, Markowitz M M, Roush G, Miller D G, Beattie E J. Isoenzyme(s) of glutathion transferase (class Mu) as a marker for the susceptibilty to lung cancer: A follow up study. Carcinogenesis. 1990; 11 33-36
23 Hirvonen A, Saarikoski S T, Linnainmaa K, Koskinen K, Husgafvel K, Mattson K, Vaino H. Glutathione S-Transferase and N-Acetyltransferase Genotypes and Asbestos-Associated Pulmonary Disorders. JNCI. 1996; 88 1853-1856
24 El-Zein R, Conforti-Froes N, Au W W. Interactions Between Genetic Predisposition and Environmental Toxicants for Developement of Lung Cancer. Environmental and Molecular Mutagenesis. 1997; 29 1-10
25 Hietanen E, Husgafvel-Pursiainen K, Vainio H. Interaction between Dose and Susceptibility to Environmental Cancer: A Short Rewiew. Environ Health Perspect. 1997; 105 Suppl.4 749-754
26 Hirvonen A. Combinations of Susceptible Genotypes and Individual Responses to Toxicants. Environ Health Perspect. 1997; 105, Suppl.4 755-758
27 Hirvonen A. Genetic factors in individual responses to environmental exposures. J Occup Environ Med. 1995; 37 37-43
28 Kempkes M, Golka K, Reich S, Reckwitz T. Glutathione S-transferase GSTM1 and GSTT1 null genotypes as potential risk factors for urothelial cancer of the bladder. Arch Toxicol. 1996; 71 123-126
29 Seidegård J, Ekström G. The role of human glutathione transferases and epoxide hydrolases in the metabolism of xenobiotics. Environ Health Perspect. 1997; 105,Suppl.4 791-799
30 Lang N P. Acetylation as an Indicator of Risk. Environ Health Perspect. 1997; 105, Suppl.4 763-766
31 Soskolne C L. Ethical, social, and legal issues surrounding studies of susceptible populations and individuals. Environ Health Perspect. 1997; 105, Suppl.4 837-841
32 Doerffer K, Unrau P. Cancer Genes and Risk Assessment. Health Phys. 1998; 74 173-180
33 Khoury M J, Little J. Human genome epidemiologic reviews: The beginning of something HuGE. Am J Epidemiol. 2000; 151 2-3
34 Cotton S C, Sharp L, Little J, Brockton N. Glutathione S-transferase polymorphisms and colorectal cancer: A HuGE review. Am J Epidemiol. 2000; 151 7-32
35 Ashley-Koch A, Yang Q, Olney R S. Sickle hemoglobin (HbS) allele and sickle cell disease: A HuGE review. Am J Epidemiol. 2000; 151 839-845
36 Brockton N, Little J, Sharp L, Cotton S C. N-acetyltransferase polymorphisms and colorectal cancer: A HuGE review. Am J Epidemiol. 2000; 151 846-861
37 Botto L D, Yang Q. 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: A HuGE review. Am J Epidemiol. 2000; 151 862-877
38 Dorman J S, Bunker C H. HLA-DQ locus of the human leucocyte antigen complex and type 1 diabetes mellitus: A HuGE review. Epidemiol Rev. 2000; 22 218-227
39 Kelada S N, Shelton E, Kaufmann R B, Khoury M J. Delta-aminolaevulinic acid dehydratase genotype and lead toxicity: A HuGE review. Am J Epidemiol. 2001; 154 1-13
40 Geisler S A, Olshan A F. GSTT1, and risk of squamous cell carcinoma of the head and neck: A mini-HuGE review. Am J Epidemiol. 2001; 154 95-105
41 Boone C W, Kellof G J, Malone W E. Identification of candidate cancer chemopreventive agents and their evaluation in animal models and human clinical trials: A review. Cancer Res. 1990; 50 2-8
42 Vineis P, D’Amore F, Working G roup on the Epidemiology of Hematolymphopoetic Malignancies in Italy. The role of occupational exposure and immunodeficiency in B-cell malignancies. Epidemiology. 1992; 3 266-270
43 Zahm S H, Blair A. Pesticides and Non-Hodgkin’s Lymphoma. Cancer Res. 1992; 52 5485s-5488s
44 Diel F, Schock B, Modi R, Schrimpf D, Mitsche T, Borck H, Diel E. Wirkungen von Pyrethroiden auf menschliche Lymphozyten in vitro. Umwelt & Gesundheit. 1995; 3 70-75
45 Roboz J, Greaves J, Bekesi J G. Polybrominated biphenyls in model and environmentally contaminated human blood: Protein binding and immunotoxicological studies. Environ Health Perspect. 1985; 60 107-113
46 Stehr-Green P A, Naylor P H, Hoffmann R E. Diminished thymosin alpha-1 levels in persons exposed to 2,3,7,8-Tertrachlorodibenzo-p-dioxin. J Toxicol Environ Health. 1989; 28 285-295
47 Kiecolt-Glaser J K, Glaser R. Psychoneuroimmunology and cancer: Fact or fiction?. Eur J Cancer. 1999; 35 1603-1607
48 Wu H, Wang J, Cacioppo J T, Glaser R, Kiecolt-Glaser J K, Malarkey W B. Chronic stress associated with spousal caregiving of patients with Alzheimer's dementia is associated with downregulation of B-lymphocyte GH mRNA. J Gerontol A Biol Sci Med Sci. 1999; 54 M212-M215
49 Kiecolt-Glaser J K. Norman Cousins Memorial Lecture 1998. Stress, personal relationships, and immune fuction: health implications. Brain Behav Immun. 1999; 13 61-72
50 Holden R J, Pakula I S, Mooney P A. An immunological model connecting the pathogenesis of stress, depression an carcinoma. Medical Hypothesis. 1998; 51 309-314
51 Knekt P, Raitasalo R, Heliövaara M, Lehtinen V, Pukkala E, Teppo L, Maatela J, Aromaa A. Elevated lung cancer risk among persons with depressed mood. Am J Epidemiol. 1996; 144 1096-1103
52 Penninx B WJH, Guralnik M P, Ferrucci L, Cerhan J R, Wallace R B, Havlik R J. Chronically Depressed Mood and Cancer Risk in Older Persons. JNCI. 1998; 90 1888-1893
53 Lander E S. et al . Initial sequencing and analysis of the human genome. Nature. 2001; 409 860-921
54 Venter J C, Adams M D, Myers E W. et al . The sequence of the human genome. Science. 2001; 291 1304-1351
55 Marth G, Yeh R, Minton M, Donaldson R, Li Q, Davenport R, Miller R D, Kwok P Y. Single-nucleotid polymorphisms in the public databases: How useful are they?. Nature Genetics. 2001; 27 371-372
56 Wjst M. Checklisten zu Design, Durchführung und Datenanalyse in der molekularen Epidemiologie. Med Genetik. 2000; 12 416-417
57 Schulte P A. A conceptual and historical framework for molecular epidemiology. Schulte PA, Perera F Molecular epidemiology San Diego New York Boston London Sydney Tokyo Toronto; Academic Press 1993: 3-44
58 Schulte P A, Perera F P. Transitional studies. Toniolo P, Boffetta P, Shuker DEG, Rothman N, Hulka B, Pearce N Application of Biomarkers in Cancer Epidemiology. IARC Scientific Publications No. 142 Lyon; International Agency for Research on Cancer 1997: 19-29
59 Potter J D. Logistics and design issues in the use of biological samples in observational epidemiology. Toniolo P, Boffetta P, Shuker DEG, Rothman N, Hulka B, Pearce N Application of Biomarkers in Cancer Epidemiology. IARC Scientific Publications No. 142 Lyon; International Agency for Research on Cancer 1997: 31-8
60 Armstrong B K, White E, Saracci R. Validity and reliability studies. Principles of exposure measurement in epidemiology. Monographs on epidemiology and biostatistics. v. 21 Oxford; Oxford University Press 1994: 78-114
61 Vineis P. Sources of variation in biomarkers. Toniolo P, Boffetta P, Shuker D, Rothman N, Hulka B, Pearce N Application of biomarkers in cancer epidemiology. IARC Scientific Publications No. 142 Lyon; International Agency for the Research on Cancer (IARC) 1997: 59-71.
62 Altman D G. Practical statistics for medical research. London; Chapman & Hall 1991
63 Latza U, Wilhelm D, Seyfarth M, Davis S, McKnight B, Stein H. Soluble cytokine receptor CD30 in atopic disorders: A case-control study. Clin Exp Allergy. 1999; 29 97-104
64 Rose G. Preventive cardiology: What lies ahead ?. Prev Med. 1990; 19 97-104
65 Deutsche A rbeitsgemeinschaft Epidemiologie (DAE). Leitlinien und Empfehlungen zur Sicherung von Guter Epidemiologischer Praxis (GEP). Gesundheitswesen. 2000; 62 295-302

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