It is important to recognize that it is the power and informativeness of GWAS themselves that drive the concept of mechanism-based disease subtypes ( Figure 2). Host Genetic Grist for the Metagenetic Mill These concepts will guide the design and interpretation of future experiments that seek to dissect the pathophysiologic mechanisms underlying a number of complex diseases and to identify more effective approaches for their treatment and prevention. These two interrelated concepts, therefore, define T1D, CD, and UC as metagenetic ( Box 1), rather than simply “genetic,” diseases. In this view, disease genetics may be combinatorial with different host-gene-microbial interactions, contributing to the pathogenesis of disease in subsets of patients. Two concepts are emphasized and integrated herein: (1) that single disease diagnoses are unlikely to be single phenotypes and may instead be the sum of multiple mechanism-based disease subsets, and (2) that the interactions of individual microorganisms and their genomes with specific host genes or pathways underpin the relationship between genotype and phenotype in these complex diseases. By peering through the lens of recent studies on CD, UC, and T1D, this review seeks to delineate emerging concepts in research on complex inflammatory diseases and to comment on the implications of these concepts for the interpretation of genetic and pathogenetic data.
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