During the last decade, the unfolding of the several genomes, including the human, and a parallel rapid development of new high-through-put genome (DNA) screening technologies have radically changed the terms and conditions for how medical research can be performed. Since the success of dismantling genetic causes of many Mendelian disorders (i.e. single gene disorders), genome-wide association studies (GWAS) have not claimed equal success for complex disorders (like CAD, MI and stroke). To reveal the full complexity of gene-environment interactions that lead to these disorders, alternative strategies than to seek isolated DNA variants or genes one-by-one in genotype-phenotype associations are needed.

One key aspect of the molecular pathology underlying complex traits is that changes in the macro- environment (reflected in toxic environments, lifestyle and food intake over time) gradually alters the micro-environments in tissues and cells. Importantly, these shifts of the micro-environments have consequences for gene regulation in altering the effects a given set of DNA variants (like single nucleotide polymorphism, SNPs) have on a biological function or dysfunction (i.e. disease development) in a given tissue.

Thus, for complex diseases (largely driven by changes in macro-environmental factors), it is important to consider genetic risk factors in combination with different sets of micro-environments. The implication being that future clinical studies trying to define molecular causes of complex traits need, in parallel to DNA and clinical phenotypes, to include intermediate (between DNA and phenotype) measurements (also referred to as intermediate phenotypes) reflecting the combined effects of DNA variation (i.e. SNPs, and other types of DNA variation) and the local microenvironment. As of today, the most well-established global measurement of intermediate phenotypes is that of gene expression mainly reflected by mRNA levels and other sources of RNAs. Gene expression in disease-relevant organs/tissues reflects the combined effects of the micro-environment and inherited DNA variants.