Individualization of Treatment Regimes Based Upon Genetic Profile
Cardiac hypertrophy in response to hemodynamic overload or myocardial injury increases myocardial mass in part by altering gene expression. Messenger RNA profiles for hypertrophy and heart failure are highly conserved between species and critical transcriptional activators of this program, such as MEF2 downstream of Gq, have been well defined. It is increasingly recognized that transcriptional repression acts in concert with transcriptional activation to coordinate expression of genes, and identification of small, non-coding microRNAs (miRs) that negatively regulate production of protein products from messenger RNA (mRNA) transcripts by binding to complementary sequences in the 3’UTR of target mRNAs has provided fresh insight into the basic mechanisms that balance gene expression.
We described a program of cardiac-expressed miRs that are dynamically regulated in human heart failure, analogous to that for mRNAs (Circulation. 119:1263-71, 2009, pdf), and have since used novel deep resequencing techniques combining multiplexed PCR, genetic bar-coding and pooled seqeuncing to examine microRNA targeting in different cardiac diseases (Proc Nat Acad Sci USA. 109:19864-9, 2012, pdf and others). Similar advanced genomics approaches have been developed to examine genetic variation within the exons of genes that cause familial hypertrophic and dilated cardiomyopathies.