A Practice Approach for Identifying Previously Unsuspected Environmental Contributors to Systemic Lupus Erythematosus and Other Complex Diseases. (Commentary)

Foster, Morris W., Aston, Christopher E., Environmental Health Perspectives

Existing medical records and health surveys provide insights into potential environmental contributors to complex chronic diseases. Those recognizable risks (e.g., workplace exposures and behaviors including smoking) do not, however, exhaust the domain of potential environmental contributors. Qualitative ethnographic investigation can be used to generate statistically testable hypotheses about environmental contributors to complex disease that otherwise would not be recognized as such. Consequently, we can empirically specify lifestyle beliefs and behaviors usually summarized by proxy identities such as race, ethnicity, gender, class, and culture. The investigation of potential environmental contributors to complex diseases may be particularly useful in confirming or disconfirming suggestive or established linkages and for indicating the kind of gene-environment interaction that may be involved. Key words: complex disease, gene-environment interaction, research design.

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Sequencing of the human genome and development of powerful analytic techniques such as neural networks have greatly improved our ability to identify genetic contributors to disease susceptibility, particularly for complex diseases in which those contributors are non-Mendelian. However, the additional role of other nongenetic environmental factors can confuse both those environmental effects (which may manifest only in genetically susceptible individuals) and genetic effects (which may manifest only when there is a history of exposure to environmental contributors) (Ottman 1996). Consequently, the investigation of environmental factors may be especially useful in identifying and confirming a specific gene, haplotype, or polygenic combination responsible for disease susceptibility and in understanding the functional mechanism by which that susceptibility is expressed as a disease. Thus, although the analysis of gene-environmental interaction is less problematic after a specific genetic contributor to a complex disease has been identified, the study of environmental contributors can be a valuable aid in making that identification, particularly when linkages are established based on genome scans and marker data are available for families (Ottman 1996). The last 2 years have seen rapid development of methods to analyze such gene-environmental interactions in a variety of study designs [e.g., Blangero et al. 2001 (pedigrees); Gauderman and Siegmund 2001 (sib pairs); Eaves and Sullivan 2001 (parent-child triads); Andrieu and Goldstein 1998 (for a review of earlier methods)].

Getting Beyond the Usual Suspects

These new, powerful analytic techniques for including gene-environment interaction are pointless, however, if the environmental measures being used are ill conceived or imprecise. Unlike genomic data, however, environmental data are not discretely segmented into linear sequences of base pairs that can be read using a standardized technology. Although one can determine "the" genetic factor by moving along this linear genome using an increasing gradient of evidence for association, there is no clear "next" environmental factor to consider if the current candidate is suggestive but not convincing. Instead, identification of candidate environmental factors for quantitative analysis often depends on qualitative observation and surmise.

Before we can count manifestations of an environmental factor and put that number in a 2 x 2 table, we first must recognize it as significant enough to enumerate and correlate. To a great extent, that recognition is both structured and limited by our preexisting cultural and linguistic categories for identifying behaviors and exposures as discrete phenomena. Linguistic anthropologists long have observed that those categories vary from one language community to another, serving to limit speakers' intuitive awareness of the world around them (Duranti 1997). No single language or culture provides a comprehensive or objective categorization of all possible human behaviors and exposures that may contribute to susceptibility to, or higher risks for, a complex disease.

Most efforts to identify environmental contributors have focused on the "usual suspects"--behaviors and exposures that have been recognized as discrete categories that may affect health (Cooper et al. 1999). Researchers often decontextualize these usual suspects from the social and cultural settings in which they occur, analyzing them as discrete, isolated events rather than as components of patterned lifestyles. Arguably, there is a need to develop a more explicit method for identifying candidate environmental contributors to complex diseases beyond those factors already categorized discretely in medical and other records (e.g., medications, viral exposures, birth order, occupations, geographic residences, environmental toxins). Such an approach would be complementary to ongoing genetic linkage studies for which candidate genes or haplotypes have been suggested or established but not confirmed. For example, linkage studies of systemic lupus erythematosus (SLE) pedigrees have identified more than 50 established or suggestive linkages, although none of these has yet been confirmed by the molecular characterization of an SLE disease gene (Kelly et al. 2002). At the same time, environmental associations with such existing categories as smoking, birth order, and Epstein-Barr virus have been suggested for SLE. These linkages usually …

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Publication information: Article title: A Practice Approach for Identifying Previously Unsuspected Environmental Contributors to Systemic Lupus Erythematosus and Other Complex Diseases. (Commentary). Contributors: Foster, Morris W. - Author, Aston, Christopher E. - Author. Journal title: Environmental Health Perspectives. Volume: 111. Issue: 4 Publication date: April 2003. Page number: 593+. © 2006 National Institute of Environmental Health Sciences. COPYRIGHT 2003 Gale Group.

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