Complementing the Genome with an “Exposome”: The Outstanding Challenge of Environmental Exposure Measurement in Molecular Epidemiology

Abstract

The sequencing and mapping of the human genome provides a foundation for the elucidation of gene expression and protein function, and the identification of the biochemical pathways implicated in the natural history of chronic diseases, including cancer, diabetes, and vascular and neurodegenerative diseases. This knowledge may consequently offer opportunities for a more effective treatment and improved patient management. Genetic research of this kind captures the public imagination in a positive manner and attracts political attention. For example, the 2003 UK Government White Paper on genetics (1), entitled “Our inheritance, our future: realising the potential of genetics in the National Health Service,” highlighted the opportunities for tailored drug treatments and gene therapy flowing from the sequencing and mapping of the human genome. However, it was notable that this influential document also drew attention to the use of genetic testing to identify individuals at greatest susceptibility to chronic diseases and the possibilities this raises for disease prevention. Application of genetics in this context moves away from the clinic towards the population and the observational methods of epidemiology. The fruit of this research in terms of reduced morbidity and mortality is therefore to be predominantly realized through public health measures.It is well known that the majority of genetic variants or single nucleotide polymorphisms in the human genome are of low penetrance, including genes implicated in metabolism of environmental chemicals, immunity, lipid metabolism, and hemostasis among others. The high prevalence of these single nucleotide polymorphisms means that despite their low penetrance, they may substantially contribute to population disease burden (2). Nevertheless, the majority will do so only in the presence of specific environmental exposures that in themselves are of low penetrance. Environmental exposures are acknowledged to play an overwhelmingly important role in those common chronic diseases mentioned above, which constitute the major health burden in economically developed countries (3, 4). Despite this, many exposure-disease associations remain ill defined and the complex interplay with genetic susceptibility is only beginning to be addressed. This raises the question as to whether fundamental knowledge about genetics will improve understanding of disease etiology at the population level.The new generation of mega-cohort studies, including the UK Biobank or similar proposed US and Asian cohorts (5-8), provides the framework for such investigations of genetic variation, environment, lifestyle, and chronic disease. At the same time, they represent substantial investment. For example, UK Biobank will recruit half a million people at a cost of around £60 million ($110 million) in the initial phase. The proposal to establish a “Last Cohort” of 1 million people in the United States (7) or a similar-sized Asian cohort (8) would presumably exceed this sum. In each case, the high cost is heavily influenced by the collection and banking of biological material. This expense is predicated on the assumption that biochemical and molecular measures on this material will resolve the etiologic questions alluded to above. It is self-evident that unraveling of complex environmental and genetic aetiologies demands that both environmental exposures and genetic variation are reliably measured. Advances in statistical methods and in bioinformatics in relation to large data sets are also of critical importance.The development of biomarkers is one avenue to improved measurement of exposure, susceptibility (including genetic), and disease in population studies, and the field of molecular cancer epidemiology is founded on this trinity of biomarker categories (9). The characterization of disease can be improved by modern histopathology, particularly the application of sophisticated molecular markers to subcategorize tumors to homogenous groups within which etiology or therapy can be better defined (10, 11). In parallel to advances in disease classification, however, the balance of efforts to improve the measurement of genetic and environmental risk factors has dramatically changed over the last 15 years in a way that has been less than ideal.The ease of genotyping following the introduction of the PCR in the late 1980s and 1990s saw a major shift in effort and resources, away from development of accurate exposure biomarkers towards the conduct of gene-disease association studies. Allied to the relatively trivial technical demands of genotyping, these measures, by consequence of the fact that they were unchanging over time, were well suited to classic case-control study design. For laboratories involved in molecular cancer epidemiology, gene-disease association studies offered rapid gains in research output. The literature is now replete with meta-analyses of these data. The studies that have been conducted have,