Integrated genomic approaches implicate osteoglycin (Ogn) in the regulation of left ventricular mass

Abstract

Left ventricular mass (LVM) and cardiac gene expression are complex traits regulated by factors both intrinsic and extrinsic to the heart. To dissect the major determinants of LVM, we combined expression quantitative trait locus1 and quantitative trait transcript2 (QTT) analyses of the cardiac transcriptome in the rat. Using these methods and in vitro functional assays, we identified osteoglycin (Ogn) as a major candidate regulator of rat LVM, with increased Ogn protein expression associated with elevated LVM. We also applied genome-wide QTT analysis to the human heart and observed that, out of ~22,000 transcripts, OGN transcript abundance had the © 2008 Nature Publishing Group Correspondence should be addressed to T.J.A. (t.aitman@csc.mrc.ac.uk) or S.A.C. (stuart.cook@imperial.ac.uk).. 11 These authors contributed equally to this work. AUTHOR CONTRIBUTIONS The study was designed by S.A.C., E.P. and T.J.A.; S.A.C. obtained funding, supervised the study and coordinated the collaborations; R.S. performed PCR-based experiments and genotyping; H.L. and M.K.K. generated rat microarray data; B.S. and Y.M.P. generated human microarray data; M.B. generated immunofluorescence confocal micrographs; R.S. and H.L. performed cell culture and cloning experiments; R.S., B.S. and M.B. performed immunoblotting; P.J.M. and R.S. performed in vivo analyses in Ogn knockout mice; E.S.T., L.M.C., M.D.W. and G.W.C. provided and genotyped the Ogn knockout mice; N.H. and J.F. carried out sequence analysis of Ogn; T.W.K., V.K. and M.P. provided telemetric blood pressure data; P.P.P. provided human tissues for protein studies; S.K.P., D.J.P. and C.K. provided the human cardiac MRI data; E.P. designed, interpreted and supervised all statistical analyses; E.P., I.G. and R.S. performed statistical and bioinformatic analyses and were aided by J.M.; and E.P. and S.A.C. wrote the manuscript.Note: Supplementary information is available on the Nature Genetics website.Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions Europe PMC Funders GroupAuthor Manuscript Nat Genet. Author manuscript; available in PMC 2009 September 11. Elevated indexed LVM is a major cause of morbidity and mortality and is regulated, in part, by hemodynamic indices3. However, only a small proportion of LVM variation is determined by hemodynamic effects4, and it has been proposed that genetic influences may also be important5,6. Many studies have shown that gene expression is heritable and that the genetic control of transcription affects physiological traits and disease phenotypes1,7. We have shown that gene transcription is highly heritable in the rat heart8, which led us to hypothesize that the genetic control of cardiac gene expression may be important in regulating LVM. Here, we used an integrated approach combining correlation of expression quantitative trait loci (eQTL)1 and genome-wide expression profiles with physiological traits, previously designated as quantitative trait transcript (QTT) analysis2, to ide...

Osteoglycin Prevents Cardiac Dilatation and Dysfunction After Myocardial Infarction Through Infarct Collagen Strengthening

“…Extensive exploration of inflammation, myofibroblast differentiation, and signaling, as well as cardiomyocyte cytoskeletal properties and hypertrophy could not reveal differences in these factors that could contribute to increased cardiac rupture, mortality, or failure in osteoglycin null mice. Although previous studies demonstrated a role for osteoglycin in cardiac hypertrophy after angiotensin infusion, 13 our data do not support a role for osteoglycin in cardiomyocyte hypertrophy. This may be because of the differences in the pathophysiology of the models.…”

“…This may be because of the differences in the pathophysiology of the models. In the study performed by Petretto et al, 13 hypertrophy was assessed by LV mass rather than a histological analysis of cardiomyocyte cross-sectional area. Furthermore we, and others, have found that cardiac fibroblasts express high levels of osteoglycin as compared with cardiac myocytes.…”

“…12 Recently, it was identified as a marker of cardiac hypertrophy in genome-wide analysis of the human heart. 13 Osteoglycin is a class III member of the small leucine-rich proteoglycans, a distinct group of extracellular proteoglycans that may affect matrix integrity through their central leucine-rich region, which is flanked by cysteine-rich domains.…”

The Progression of Hypertensive Heart Disease

“…Because there is strong evidence for heritability of LV mass, including observations from studies of the general population, 19 sibling studies, 20 and recent longitudinal twin studies, 21 considerable interest exists in identifying putative genetic risk factors that modulate LV mass. These efforts have progressed from candidate gene association studies 22 to genome-wide expression analyses with the use of microarray data 23 and genome-wide association studies 24 but remain in their relatively early stages and have not yet yielded results that have translated into the clinical arena. It seems likely that multiple variants, each with modest effect size, will be involved in modulating complex traits, 25 including LV mass.…”

Analysis of candidate genes of QTL and chromosomal regions for essential hypertension in the rat model

“…The other noteworthy gene in this QTL is osteoglycin (OGN). In a quantitative trait transcript (QTT) analysis study of the cardiac transcriptome in the rat, Petretto et al [16] showed that OGN is a key regulator of left ventricular mass (LVM) in rats, mice and humans, and suggested that OGN modifies the hypertrophic response to extrinsic factors such as hypertension and aortic stenosis.…”