Integrated Computational and Experimental Analysis of the Neuroendocrine Transcriptome in Genetic Hypertension Identifies Novel Control Points for the Cardiometabolic Syndrome
Year: 2012
Type: article
Abstract: BACKGROUND: Essential hypertension, a common complex disease, displays substantial genetic influence. Contemporary methods to dissect the genetic basis of complex diseases such as the genomewide association study are powerful, yet a large gap exists between the fraction of population trait variance explained by such associations and total disease heritability. METHODS AND RESULTS: We developed a novel, integrative method (combining animal models, transcriptomics, bioinformatics, molecular biology, and trait-extreme phenotypes) to identify candidate genes for essential hypertension and the metabolic syndrome. We first undertook transcriptome profiling on adrenal glands from blood pressure extreme mouse strains: the hypertensive BPH (blood pressure high) and hypotensive BPL (blood pressure low). Microarray data clustering revealed a striking pattern of global underexpression of intermediary metabolism transcripts in BPH. The MITRA algorithm identified a conserved motif in the transcriptional regulatory regions of the underexpressed metabolic genes, and we then hypothesized that regulation through this motif contributed to the global underexpression. Luciferase reporter assays demonstrated transcriptional activity of the motif through transcription factors HOXA3, SRY, and YY1. We finally hypothesized that genetic variation at HOXA3, SRY, and YY1 might predict blood pressure and other metabolic syndrome traits in humans. Tagging variants for each locus were associated with blood pressure in a human population blood pressure extreme sample with the most extensive associations for YY1 tagging single nucleotide polymorphism rs11625658 on systolic blood pressure, diastolic blood pressure, body mass index, and fasting glucose. Meta-analysis extended the YY1 results into 2 additional large population samples with significant effects preserved on diastolic blood pressure, body mass index, and fasting glucose. CONCLUSIONS: The results outline an innovative, systematic approach to the genetic pathogenesis of complex cardiovascular disease traits and point to transcription factor YY1 as a potential candidate gene involved in essential hypertension and the cardiometabolic syndrome.
Institutions: Scripps Research Institute, Johns Hopkins University, University of California, Los Angeles, Queen Mary University of London, Indian Institute of Technology Madras, Johns Hopkins Medicine, University of California San Diego, VA San Diego Healthcare System, William Harvey Research Institute
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Funders: National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Research Resources, National Center for Advancing Translational Sciences, National Institute on Minority Health and Health Disparities
Awards: Hypertensive kidney disease: Novel pathogenic and therapeutic pathway, G1938206167, G19840586, San Diego EXPORT Comprehensive NCMHD Research Center, Sympathetic Neuroeffector Junctions & Blood Pressure, San Diego Clinical and Translational Research Institute, Discovering the Genetic Basis of Hypertension, Nephrology Training Grant, Genomic Predictors of Combat Stress Vulnerability and Resilience, G8266243303, UC San Diego Clinical and Translational Research Institute, General Clinical Research Center
OpenAlex ID: W2102358321