The impact of new research technologies on our understanding of environmental causes of disease: the concept of clinical vulnerability

Abstract

In spite of decades of epidemiological research, the etiology and causal patterns for many common diseases, such as breast and colon cancer or neurodegenerative diseases, are still largely unknown. Such chronic diseases are likely to have an environmental origin. However, "environmental" risks have been often elusive in epidemiological studies. This is a conundrum for current epidemiological research. On the other side, the relative contribution of genes to chronic diseases, as emerging from GWAS, seems to be modest (15-50% increase in disease risk). What is yet to be explored extensively is a model of disease based on long-term effects of low doses of environmental exposures, incorporating both genetic and acquired susceptibility ("clinical vulnerability"), and the cumulative effects of different exposures. Such a disease model would be compatible with the weak associations found by GWAS and the still elusive role of many (low-level) environmental exposures. We also propose that the introduction of "-omic" high-throughput technologies, such as transcriptomics, proteomics and metabolomics, may provide, in the next years, powerful tools to investigate early effects of environmental exposures and understand the etiology of common diseases better, according to the "clinical vulnerability model". The development of "-omics", in spite of current limitations and lack of sound validation, could greatly contribute to the elucidation of the disease model we propose.

Figure 1

Cumulative risk of lung cancer by rs8034191 genotype. Relevance of smoking and of rs8034191 genotype to lung cancer mortality in men aged 45-75 years. Cumulative risk (in the absence of other causes of death) based on national lung cancer death rates for men in Poland in the year 2000, assuming that the prevalence of current smoking, former smoking, and never smoking are as in this study and that the relative risks for lung cancer incidence and mortality are similar (Hung et al 2008) [1].

Figure 2

Vulnerability plus exposure events change the physiological state, but a reserve is present. When the reserve is overtaken, clinical manifestations appear. From http://www.sahsu.org/jubilee_presentations/Anderson.ppt#392,21, courtesy of R Anderson.