Integrated computational and experimental analysis of the neuroendocrine transcriptome in genetic hypertension identifies novel control points for the cardiometabolic syndrome.
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.


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.
Department of Bioengineering, University of California at San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0838, USA.
Ryan S
RS
Friese
Chun
C
Ye
Caroline M
CM
Nievergelt
Andrew J
AJ
Schork
Nitish R
NR
Mahapatra
Fangwen
F
Rao
Philip S
PS
Napolitan
Jill
J
Waalen
Georg B
GB
Ehret
Patricia B
PB
Munroe
Geert W
GW
Schmid-Schönbein
Eleazar
E
Eskin
Daniel T
DT
O'Connor
D000311:Adrenal Glands / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D001794:Blood Pressure / Q000235:genetics; D019295:Computational Biology / Q000379:methods*; D004742:Enhancer Elements, Genetic / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D006973:Hypertension / Q000235:genetics*; D008156:Luciferases / Q000378:metabolism; D008297:Male; D015201:Meta-Analysis as Topic; D024821:Metabolic Syndrome / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009490:Neurosecretory Systems / Q000378:metabolism*; D059372:Nucleotide Motifs / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000235:genetics; D059467:Transcriptome / Q000235:genetics*
D012333:RNA, Messenger; D014157:Transcription Factors; D008156:Luciferases