Introduction

Genes, Environment, Health, and Disease: Facing up to Complexity
Teri A. Manolio, Francis S. Collins

National Human Genome Research Institute, NIH, Bethesda, Md., USA

Address of Corresponding Author

Hum Hered 2007;63:63-66 (DOI: 10.1159/000099178)

  Abstract

Sorry, there is no abstract. Read the first few lines of the text instead!

The deciphering of the human genome sequence, the DNA instruction book that makes us not only uniquely human but also unique as individuals, has provided unparalleled opportunities for identifying the relationship of genetic variation to health and disease. Yet as we move from single-gene diseases, in which a single misspelled base-pair can lead to such devastating conditions as sickle cell disease or Hutchinson-Gilford progeria syndrome, to complex diseases involving interactions among many interacting genes of small effect and many potential environmental modifiers, we need to develop tools to unravel the complexity of these interacting risk factors. Even in single-gene diseases, the frequent inter-individual variability in disease manifestations and course suggests the presence of modifiers for these presumably simple diseases, whether due to differing genetic backgrounds or differing environmental exposures, that are only beginning to be identified [1].

Copyright © 2006 S. Karger AG, Basel

  References

1.

Drumm ML, Konstan MW, Schluchter MD, Handler A, Pace R, Zou F, Zariwala M, Fargo D, Xu A, Dunn JM, Darrah RJ, Dorfman R, Sandford AJ, Corey M, Zielenski J, Durie P, Goddard K, Yankaskas JR, Wright FA, Knowles MR, Gene Modifier Study Group. Genetic modifiers of lung disease in cystic fibrosis. N Engl J Med 2005;353:1443-1453.

2.

Hirschhorn JN, Daly MJ: Genome-wide association studies for common diseases and complex traits. Nat Rev Genet 2005;6:95-108.

3.

Thomas DC: Are we ready for genome-wide association studies? Cancer Epidemiol Biomarkers Prev 2006;15:595-598.

4.

Qian GS, Ross RK, Yu MC, Yuan JM, Gao YT, Henderson BE, Wogan GN, Groopman JD: A follow-up study of urinary markers of aflatoxin exposure and liver cancer risk in Shanghai, People's Republic of China. Cancer Epidemiol Biomarkers Prev 1994;3:3-10.

5.

Selikoff IJ, Hammond EC, Churg J: Asbestos exposure, smoking, and neoplasia. JAMA 1968;204:106-112.

6.

Cambien F, Poirier O, Lecerf L, Evans A, Cambou JP, Arveiler D, Luc G, Bard JM, Bara L, Ricard S, et al: Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature 1992;359:641-644.

7.

Jacques PF, Bostom AG, Williams RR, Ellison RC, Eckfeldt JH, Rosenberg IH, Selhub J, Rozen R: Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation 1996;93:7-9.

8.

Small KM, Wagoner LE, Levin AM, Kardia SL, Liggett SB: Synergistic polymorphisms of beta1- and alpha2C-adrenergic receptors and the risk of congestive heart failure. N Engl J Med 2002;347:1135-1142.

9.

Howard TD, Koppelman GH, Xu J, Zheng SL, Postma DS, Meyers DA, Bleecker ER: Gene-gene interaction in asthma: IL4RA and IL13 in a Dutch population with asthma. Am J Hum Genet 2002;70:230-236.

10.

Patsch W, Sharrett AR, Chen IY, Lin-Lee YC, Brown SA, Gotto AM Jr, Boerwinkle E: Associations of allelic differences at the A-I/C-III/A-IV gene cluster with carotid artery intima-media thickness and plasma lipid transport in hypercholesterolemic-hypertriglyceridemic humans. Arterioscler Thromb 1994;14:874-883.

11.

Jerrard-Dunne P, Sitzer M, Risley P, Steckel DA, Buehler A, von Kegler S, Markus HS; Carotid Atherosclerosis Progression Study. Interleukin-6 promoter polymorphism modulates the effects of heavy alcohol consumption on early carotid artery atherosclerosis: the Carotid Atherosclerosis Progression Study (CAPS). Stroke 2003;34:402- 407.

12.

Feinleib M: Data bases, data banks and data dredging: The agony and the ecstasy. J Chronic Dis 1984;37:783-790.

13.

Furberg CD, Byington RP: What do subgroup analyses reveal about differential response to beta-blocker therapy? The Beta-Blocker Heart Attack Trial experience. Circulation. 1983;676(Pt 2):I98-101.

14.

National Institutes of Health Consensus Development Panel. National Institutes of Health Consensus Development Conference Statement: phenylketonuria: screening and management, October 16-18, 2000. Pediatrics 2001;108:972-982.

15.

Hacein-Bey-Abina S, von Kalle C, Schmidt M, Le Deist F, Wulffraat N, McIntyre E, Radford I, Villeval JL, Fraser CC, Cavazzana-Calvo M, Fischer A: A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N Engl J Med 2003;348:255-256.

16.

Raper SE, Chirmule N, Lee FS, Wivel NA, Bagg A, Gao GP, Wilson JM, Batshaw ML: Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol Genet Metab 2003;80:148-158.

17.

Kotti S, et al: Strategy for detecting susceptibility genes with weak or no marginal effect. Human Hered 2007;2:85-92.

18.

Culverhouse R, et al: The use of the restricted partition method with case-control data. Human Hered 2007;2:93-100.

19.

Kraft P, et al: Exploiting gene-environment interaction to detect genetic associations. Human Hered 2007;2:111-119.

20.

Whittemore AS: Assessing environmental modifiers of disease risk associated with rare mutations. Human Hered 2007;2:134-143.

21.

Tung L, et al: The impact of genotype misclassification errors on the power to detect a gene-environment interaction using cox proportional hazards modeling. Human Hered 2007;2:101-110.

22.

Moore JH, et al: Symbolic modeling of epistasis. Human Hered 2007;2:120-133.

23.

Musani SK, et al: Detection of gene x gene interactions in genome-wide association studies of human population data. Human Hered 2007;2:67-84.

24.

Sung YJ, et al: Accounting for epistasis in linkage analysis of general pedigrees. Human Hered 2007;2:144-152.

25.

Campbell CD, Ogburn EL, Lunetta KL, Lyon HN, Freedman ML, Groop LC, Altshuler D, Ardlie KG, Hirschhorn JN: Demonstrating stratification in a European American population. Nat Genet 2005;37:868-872.

26.

Kannel WB, Dawber TR, Kagan A, Revotskie N, Stokes JI: Factors of risk in the development of coronary heart disease - six year follow-up experience; the Framingham Study. Ann Intern Med 1961;55:33-50.

27.

Kannel WB, Feinleib M, McNamara PM, Garrison RJ, Castelli WP: An investigation of coronary heart disease in families. The Framingham offspring study. Am J Epidemiol 1979;110:281-290.

28.

Hubert HB, Feinleib M, McNamara PM, Castelli WP: Obesity as an independent risk factor for cardiovascular disease: A 26-year follow-up of participants in the Framingham Heart Study. Circulation 1983;67:968-977.

29.

Kannel WB, McGee DL: Diabetes and glucose tolerance as risk factors for cardiovascular disease: the Framingham Study. Diabetes Care 1979;2:120-126.

30.

Seshadri S, Wolf PA, Beiser A, Au R, McNulty K, White R, D'Agostino RB: Lifetime risk of dementia and Alzheimer's disease. The impact of mortality on risk estimates in the Framingham Study. Neurology 1997;49:1498-1504.

31.

McAlindon TE, Wilson PW, Aliabadi P, Weissman B, Felson DT: Level of physical activity and the risk of radiographic and symptomatic knee osteoarthritis in the elderly: the Framingham study. Am J Med 1999;106:151-157.

32.

Kreger BE, Splansky GL, Schatzkin A: The cancer experience in the Framingham Heart Study cohort. Cancer 1991;67:1-6.

33.

Walter RE, Beiser A, Givelber RJ, O'Connor GT, Gottlieb DJ: Association between glycemic state and lung function: the Framingham Heart Study. Am J Respir Crit Care Med 2003;167:911-916.

34.

Leibowitz HM, Krueger DE, Maunder LR, Milton RC, Kini MM, Kahn HA, Nickerson RJ, Pool J, Colton TL, Ganley JP, Loewenstein JI, Dawber TR: The Framingham Eye Study monograph: An ophthalmological and epidemiological study of cataract, glaucoma, diabetic retinopathy, macular degeneration, and visual acuity in a general population of 2631 adults, 1973-1975. Surv Ophthalmol 1980;24(suppl):335-610.

35.

Gates GA, Cooper JC Jr, Kannel WB, Miller NJ: Hearing in the elderly: the Framingham cohort, 1983-1985. Part I. Basic audiometric test results. Ear Hear 1990;11:247-256.

36.

Kannel WB, Larson M: Long-term epidemiologic prediction of coronary disease. The Framingham experience. Cardiology 1993;82:137-152.

37.

Clayton DG, Walker NM, Smyth DJ, Pask R, Cooper JD, Maier LM, Smink LJ, Lam AC, Ovington NR, Stevens HE, Nutland S, Howson JM, Faham M, Moorhead M, Jones HB, Falkowski M, Hardenbol P, Willis TD, Todd JA: Population structure, differential bias and genomic control in a large-scale, case-control association study. Nat Genet 2005;37:1243-1246.

38.

Schwartz DA, Weis B, Wilson SH: The need for exposure health sciences. Environ Health Perspect 2005;113:A650.

39.

Garcia-Closas M, Rothman N, Lubin J: Misclassification in case-control studies of gene-environment interactions: Assessment of bias and sample size. Cancer Epidemiol Biomarkers Prev 1999;8:1043-1050.

40.

Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C, Henning AK, SanGiovanni JP, Mane SM, Mayne ST, Bracken MB, Ferris FL, Ott J, Barnstable C, Hoh J: Complement factor H polymorphism in age-related macular degeneration. Science 2005;308:385-389.

41.

DeWan A, Liu M, Hartman S, Zhang S, Liu DTL, Zhao C, Tam POS, Chan WM, Lam DSC, Snyder M, Barnstable C, Pang CP, Hoh J: HTRA1 Promoter Polymorphism in Wet Age-Related Macular Degeneration. Published online October 19 2006;10.1126/ science.1133807 (Science Express Reports) www.sciencexpress.org.

42.

Fung HC, Scholz S, Matarin M, Simon-Sanchez J, Hernandez D, Britton A, Gibbs JR, Langefeld C, Stiegert ML, Schymick J, Okun MS, Mandel RJ, Fernandez HH, Foote KD, Rodriguez RL, Peckham E, De Vrieze FW, Gwinn-Hardy K, Hardy JA, Singleton A: Genome-wide genotyping in Parkinson's disease and neurologically normal controls: first stage analysis and public release of data. Lancet Neurol 2006;5:911-916.

43.

Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ, Steinhart AH, Abraham C, Regueiro M, Griffiths A, Dassopoulos T, Bitton A, Yang H, Targan S, Datta LW, Kistner EO, Schumm LP, Lee A, Gregersen PK, Barmada MM, Rotter JI, Nicolae DL, Cho JH: A Genome-Wide Association Study Identifies IL23R as an Inflammatory Bowel Disease Gene. Published online October 26, 2006;10.1126/science.1135245 (Science Express Reports) www.sciencexpress.org.

  Author Contacts

Dr. Francis S. Collins
National Human Genome Research Institute
31 Center Drive, Building 31, Room 4B09
Bethesda, MD 20892-2152 (USA)
Tel. +1 301 496 0844, Fax +1 301 402 0837, E-Mail FSCollins@mail.nih.gov

  Article Information

Published online: February 2, 2007
Number of Print Pages : 4
Number of Figures : 0, Number of Tables : 0, Number of References : 43

  Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 63, No. 2, Year 2007 (Cover Date: February 2007)

Journal Editor: Devoto, M. (Philadelphia, Pa.)
ISSN: 0001-5652 (print), 1423-0062 (Online)

For additional information: http://www.karger.com/HHE

  Drug Dosage / Copyright

Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.