Integrated genomics approaches identify osteoglycin as a regulator of left ventricular mass

Introduction Increased left ventricular mass (LVM) is an independent risk factor for cardiovascular disease. Although haemodynamic factors regulating LVM have been extensively investigated, the genetic components of this clinically important phenotype remain unclear. LVM and cardiac gene expression are complex traits regulated by factors both intrinsic and extrinsic to the heart, and are well suited for study with specialised rodent genetic resources. Because gene expression is highly heritable and also because it lies between DNA sequence polymorphisms and physiological traits, genetic determinants of cardiac gene expression are good candidates for primary regulators of complex cardiac phenotypes. Methods and Results To dissect the major determinants of LVM, LVM and cardiac gene expression were measured in the rat heart from a set of 29 recombinant inbred strains derived from the spontaneously hypertensive rat and the “normal” brown Norway strain. LVM was corrected for body mass, and cardiac gene expression was quantified with Affymetrix RAE 230 2.0 microarrays (four males/strain, 6–8 weeks old, 128 microarrays). Genome-wide linkage analysis was performed on LVM and cardiac gene expression using published approaches. A previously published control point for rat LVM on chromosome 17 was confirmed and refined (log of the odds, LOD, score 4.0), and was also shown to be independent of blood pressure in this model (fig 1). Osteoglycin (Ogn) was the gene within this region that had significant genetic control (genome-wide p Conclusions Taken together, these data identify Ogn as a key regulator of LVM in rats, mice and in humans, and also that Ogn modifies the hypertrophic response to extrinsic factors such as hypertension and aortic stenosis.