TY - JOUR
T1 - Integrated computational and experimental analysis of the neuroendocrine transcriptome in genetic hypertension identifies novel control points for the cardiometabolic syndrome
AU - Friese, Ryan S.
AU - Ye, Chun
AU - Nievergelt, Caroline M.
AU - Schork, Andrew J.
AU - Mahapatra, Nitish R.
AU - Rao, Fangwen
AU - Napolitan, Philip S.
AU - Waalen, Jill
AU - Ehret, Georg B.
AU - Munroe, Patricia B.
AU - Schmid-Schönbein, Geert W.
AU - Eskin, Eleazar
AU - O'Connor, Daniel T.
PY - 2012/8
Y1 - 2012/8
N2 - 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 betweens 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 frst 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.
AB - 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 betweens 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 frst 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.
KW - BPH mouse strain
KW - Complex trait
KW - Essential (genetic) hypertension
KW - Human genetics
KW - Metabolic syndrome
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UR - http://www.scopus.com/inward/citedby.url?scp=84868618810&partnerID=8YFLogxK
U2 - 10.1161/CIRCGENETICS.111.962415
DO - 10.1161/CIRCGENETICS.111.962415
M3 - Article
C2 - 22670052
AN - SCOPUS:84868618810
SN - 1942-325X
VL - 5
SP - 430
EP - 440
JO - Circulation: Cardiovascular Genetics
JF - Circulation: Cardiovascular Genetics
IS - 4
ER -