Review articles in prestige journal Nature Genetics

Identification of osteoglycin (Ogn) as a genetic determinant predisposing to left ventricular hypertrophy in rats, mice, and humans

Left ventricular mass (LVM) and cardiac gene expression are complex phenotypes that are regulated by factors both intrinsic and extrinsic to the heart. To dissect experimentally the major determinants of LVM indexed to body mass (LVMI), we used a panel of recombinant inbred (RI) rat strains in a novel approach that integrates genetic linkage and gene expression studies with quantitative trait transcript (QTT) analysis. Using comprehensive telemetric haemodynamic data, we controlled for the key extrinsic factors expected to influence LVMI. We generated genome-wide expression profiles across the RI panel and show that cardiac gene expression and LVMI are controlled predominantly by genetic factors as opposed to extra-cardiac stimuli. Genetic linkage analysis was used to map the cis and trans determinants of gene expression for thousands of genes across the rat genome. Genomewide QTT analysis for LVMI revealed two significant QTT clusters of cis regulated genes, one of which colocalised to a previously mapped LVMI QTL. We refined this QTL and identified functional sequence variants in Ogn, the major candidate at this locus. In translational studies, out of a possible 22,000 transcripts OGN was the most highly correlated gene with human LVMI. As observed in the rat, neither LMVI nor OGN expression correlated with haemodynamic measures in humans. Finally, we tested the functional effects of Ogn and showed that LVMI was significantly attenuated the Ogn knockout mouse. This is the first study to integrate eQTL, and QTT analyses and demonstrates the power of systems approaches for the study of complex traits.
E. Petretto, R. Sarwar, I. Grieve, H. Lu, M. K. Kumaran, P. J. Muckett, J. Mangion, B. Schroen, M. Benson, P. P. Punjabi, S. K. Prasad, D. J.P ennell, C. Kiesewetter, E. S. Tasheva, L. M. Corpuz, M. D. Webb, G. W. Conrad, T. W. Kurtz, V. Kren, J. Fischer, N. Hubner, Y. M. Pinto, M. Pravenec, T. J. Aitman, S. A. Cook: Integrated genomic approaches implicate osteoglycin (Ogn) in the regulation of left ventricular mass, Nature Genetics 40:546-552, 2008, Nature Genetics 40:538-545, 2008, IF=25.556
 

Author: pravenecbiomed.cas.cz
 

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