Abstract-Copy number variation has emerged recently as an important genetic mechanism leading to phenotypic heterogeneity.The aim of our study was to determine whether copy number variants (CNVs) exist between the spontaneously hypertensive rat (SHR) and its control strain, the Wistar-Kyoto rat, whether these map to quantitative trait loci in the rat and whether CNVs associate with gene expression or blood pressure differences between the 2 strains. We performed a comparative genomic hybridization assay between SHR and Wistar-Kyoto strains using a whole-genome array. In total, 16 CNVs were identified and validated (6 because of a relative loss of copy number in the SHR and 10 because of a relative gain). CNVs were present on rat autosomes 1, 3, 4, 6, 7, 10, 14, and 17 and varied in size from 10.0 kb to 1.6 Mb. Most of these CNVs mapped to chromosomal regions within previously identified quantitative trait loci, including those for blood pressure in the SHR. Transcriptomic experiments confirmed differences in the renal expression of several genes (including Ms4a6a, Ndrg3, Egln1, Cd36, Sema3a, Ugt2b, and Idi21) located in some of the CNVs between SHR and Wistar-Kyoto rats. In F 2 animals derived from an SHRϫWistar-Kyoto cross, we also found a significant increase in blood pressure associated with an increase in copy number in the Egln1 gene. Our findings suggest that CNVs may play a role in the susceptibility to hypertension and related traits in the SHR. (Hypertension. 2010;55:1231-1238.)Key Words: DNA copy number variations Ⅲ hypertension Ⅲ inbred SHR Ⅲ genetics Ⅲ gene expression Ⅲ microarray analysis Ⅲ blood pressure H igh blood pressure (BP; hypertension) is a major risk factor for coronary, cerebrovascular, and renal disease. Most cases of hypertension have unknown etiology and are, thus, classified as essential hypertension. Hypertension has a significant genetic contribution. Despite the progress made toward the understanding of rare monogenic forms of hypertension in humans, the genetic background of essential hypertension remains poorly understood. 1 The spontaneously hypertensive rat (SHR) is one of the most widely used genetic models for hypertension. The SHR model is characterized by hypertension, insulin resistance, hypertriglyceridemia, and hypercholesterolemia. Genetically, the SHR was derived in 1963 from inbreeding Wistar rats with the highest BPs. 2 Using linkage analysis, there have been multiple efforts to map genes influencing BP and related phenotypes in the SHR. These efforts have resulted in the successful identification of several chromosome regions containing quantitative trait loci (QTLs) regulating BP or related cardiovascular and metabolic phenotypes in the SHR. 3 Yet, despite many experiments, very few genes that underlie these QTLs have been unambiguously identified. 4 Copy number variations (CNVs), defined as gains and losses of DNA typically Ͼ1 kb and up to several megabases, are being increasingly recognized as a source of differences in genomic sequence 5-8 and have been proposed...
