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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:223.)
© 2000 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Identification of Quantitative Trait Loci for Serum Cholesterol Levels in Stroke-Prone Spontaneously Hypertensive Rats

Norihiro Kato; Tomoko Tamada; Toru Nabika; Keita Ueno; Takanari Gotoda; Chiho Matsumoto; Tomoji Mashimo; Makoto Sawamura; Katsumi Ikeda; Yasuo Nara; Yukio Yamori

From the Graduate School of Human and Environmental Studies, University of Kyoto, Kyoto (N.K., T.T., K.U., C.M., T.M., M.S., K.I., Y.Y.); the Department of Laboratory Medicine, Shimane Medical University, Izumo (T.N.); the Department of Internal Medicine, University of Tokyo, Tokyo (T.G.); and the Graduate School of Integrated Science and Art, University of East Asia, Yamaguchi (Y.N.), Japan.

Correspondence to Norihiro Kato, MD, PhD, Department of Internal Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan. E-mail nkato{at}med.teikyo-u.ac.jp

Abstract—The stroke-prone spontaneously hypertensive rat (SHRSP) has been reported to show significantly lower levels of serum total cholesterol than the normotensive control strain Wistar-Kyoto rat (WKY). Because selective inbreeding was conducted for stroke proneness, this concomitantly inherited characteristic of SHRSP may play some pathophysiological role in stroke. We evaluated the genetic determinants of the cholesterol trait by estimating heritability and subsequently by undertaking a genome-wide screen with 161 genetic markers in F₂ progeny involving SHRSP and WKY (104 male and 106 female rats). Three quantitative trait loci (QTLs) were detected on rat chromosomes 5, 7, and 15. Markers from the linked region on chromosome 15 indicated significant evidence of linkage with a maximal log of the odds (LOD) score of 7.7, whereas those on chromosomes 5 and 7 cosegregated with the trait in a sex-specific manner (the QTL close to genetic marker D5 Mit5 reached an LOD score of 7.3 in males, and that close to D7 Mit10 reached an LOD score of 3.2 in females). The male-specific QTL on chromosome 5 appeared to overlap with previously reported QTLs for stroke-associated phenotypes, but an identical gene (or genes) appeared unlikely to control these and the cholesterol traits simultaneously. In the present study, serum cholesterol levels were shown to be highly genetically determined in SHRSP (the heritability estimates are 76% in males and 83% in females), and 3 QTLs with substantial effects were identified. Further work, however, is required to clarify whether the cholesterol trait is related to the etiology of stroke or has been retained by chance through the inbreeding process in SHRSP.

Key Words: stroke • susceptibility • lipids • linkage • sex specificity

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