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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 highest correlation with LVM. We further confirmed a role for Ogn in the in vivo regulation of LVM in Ogn knockout mice. Taken together, these data implicate Ogn as a key regulator of LVM in rats, mice and humans, and suggest that Ogn modifies the hypertrophic response to extrinsic factors such as hypertension and aortic stenosis.

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Figure 1: Quantitative trait transcripts analysis of cis eQTLs with physiological traits in the rat.
Figure 2: Candidate cis-regulated genes within the rat QTL for left ventricular mass.
Figure 3: Correlation between hemodynamic indices and indexed LVM in individuals with aortic stenosis.
Figure 4: Molecular characterization of rat Ogn.
Figure 5: In vivo regulation of LVM in Ogn knockout mice.

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Acknowledgements

Mice used in this study were produced by Eli Lilly, Inc., and made available to the authors. We are grateful to R. Buchan for technical assistance, to P. Froguel, A. Angius, M. Falchi and M. Schneider for comments on the manuscript, to S. Harding (National Heart and Lung Institute, Imperial College, London) for providing the isolated adult rat cardiac myocytes and to J. Sassard (University of Lyon) for providing DNA from the Lyon rat strains. This work was primarily supported by funding from the UK Department of Health (S.A.C. and H.L.) and the British Heart Foundation (R.S., S.A.C.). In addition, studies were supported by research grants from the Medical Research Council of UK (T.J.A., S.A.C.), the Fondation Leducq (T.J.A., S.A.C., M.B.), the EU EURATools award (T.J.A., S.A.C., N.H., M.P.), the Wellcome Trust (I.G.), the Howard Hughes Medical Institute Research Scholars Program (M.P.), the Grant Agency of the Czech Republic (M.P.), the Ministry of Education of the Czech Republic (M.P., V.K.), the 2003T302 grant of the Netherlands Heart Foundation (Y.M.P), the InterCardiology Institute Netherlands (Y.M.P.), a Rubicon grant from the Netherlands Organisation for Scientific Research (NWO, to B.S.), the Wellcome Trust Functional Genomics Initiative and the Biological Atlas of Insulin Resistance (BAIR) (M.K.K.), the German National Genome Research Network (NGFN2, to N.H.), and the US National Institutes of Health's National Eye Institute EY000952 and EY13395 (G.W.C.).

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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.

Corresponding authors

Correspondence to Timothy J Aitman or Stuart A Cook.

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Supplementary Figures 1–8, Supplementary Tables 1–10, Supplementary Methods (PDF 755 kb)

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Petretto, E., Sarwar, R., Grieve, I. et al. Integrated genomic approaches implicate osteoglycin (Ogn) in the regulation of left ventricular mass. Nat Genet 40, 546–552 (2008). https://doi.org/10.1038/ng.134

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