Academic journal article Environmental Health Perspectives

Will Investments in Large-Scale Prospective Cohorts and Biobanks Limit Our Ability to Discover Weaker, Less Common Genetic and Environmental Contributors to Complex Diseases?

Academic journal article Environmental Health Perspectives

Will Investments in Large-Scale Prospective Cohorts and Biobanks Limit Our Ability to Discover Weaker, Less Common Genetic and Environmental Contributors to Complex Diseases?

Article excerpt

Increasing the size of prospective cohorts and biobanks is one approach to discovering previously unknown contributors to complex diseases, but it may come at the price of concealing contributors that are less common across all the participants in those larger studies and of limiting hypothesis generation. Prospective cohorts and biobanks constitute significant, long-term investments in research infrastructure that will have ongoing consequences for opportunities in biomedical research for the foreseeable future. Thus, it is important to think about how these major additions to research infrastructure can be designed to be more productive in generating hypotheses for novel environmental contributors to complex diseases and to help identify genetic and environmental contributors that may not be common across the larger samples but are more frequent within local or ancestral subsets. Incorporating open-ended inquiries and qualitative information about local communal and ecologic contexts and the political, economic, and other social structures that affect health status and outcome will enable qualitative hypothesis generation in those localized contexts, as well as the collection of more detailed genealogic and family health history information that may be useful in designing future studies. Using communities as building blocks for larger cohorts and biobanks presents some practical and ethical challenges but also enhances opportunities for interdisciplinary, multilevel investigations of the multifactorial contributors to complex diseases. Key words: biobanks, communities, complex disease, gene-environment interaction, prospective cohorts, qualitative methods, research design. Environ Health Perspect 113:119-122 (2005). doi:10.1289/ehp.7343 available via http://dx.doi.org/[Online 4 November 2004]

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Of the approximately 30,000 genes in the entire human genome, > 1,500 genetic variants have been discovered in which a single allele (either as a homozygote or heterozygote) is sufficient for a single gene or Mendelian disorder such as Huntington's disease to develop (National Center for Biotechnology Information 2004). However, relatively few variants have been confirmed for complex diseases such as cancer, heart disease, and diabetes in which both susceptibility genes and environmental contributors are required for the disease to develop (Botstein and Risch 2003; Hirschhorn et al. 2002). The slow pace in identifying and confirming genetic contributors for complex diseases is due primarily to the difficulties of detecting relatively weak, incremental genetic effects as well as to the possibility that even moderate or strong effects involving a genetic contributor may require the co-occurrence of one or more environmental contributors (Hodgson and Popat 2003).

Similarly, although the identity and function of some environmental contributors to complex diseases such as cancer are well known (toxicants such as asbestos, behaviors such as smoking, viruses such as human papilloma virus), almost all of these known contributors have been identified as such because they have relatively strong effects on disease susceptibility. At the same time, however, a significant proportion of environmental contributors remain unknown for many complex diseases. For example, only one-third of the breast cancer cases in the United States can be accounted for by known risk factors (Stevens 2002). The overwhelming remainder involves cither candidate risk factors that are known but have not yet been confirmed as such (which raises the cases accountable to ~50%) or risk factors that are not recognized as such at all. Moreover, even already-identified risk factors for disease such as diet, tobacco, and hormones each are composed of complicated combinations of behaviors and toxicants whose roles in carcinogenesis are not well understood (Brennan 2002). Smoking, for instance, is a contextually shaped behavior that can take a variety of often culturally specific forms as it exposes those who perform it (and others around them) to > 300 different toxicants (Chassin et al. …

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