Quantitative Trait Loci (QTLs) for Serum Cholesterol Levels in the Stroke-Prone Spontaneously Hypertensive Rats (SHRSP)

Summary

The stroke-prone spontaneously hypertensive rat (SHRSP) is an animal model of spontaneous hypertension and stroke, and has previously been reported to have significantly lower serum cholesterol levels as compared with normotensive control (WKY) rats. Interestingly, attenuation of stroke with dietary cholesterol supplementation has also been reported. To identify quantitative trait loci (QTLs) linked to the low-cholesterol phenotype in the SHRSP, we performed a genome-wide search with 161 genetic markers in 210 F2 progeny derived from SHRSP and WKY. We found that the trait was highly heritable in both males and females (genetic heritability > 70%). A QTL with major effects on cholesterol levels in both sexes has been identified on a relatively broad region of chromosome (Chr) 15 with a maximum lod score of 7.7. Detailed comparison of the linked region between the stroke-prone and stroke-resistant substrains helped to narrow the candidate region into a small segment (< 7 cM) between D15Mgh 2 and D15 Rat 2, which apparently excluded the apolipoprotein J locus from candidates. We also found additional two loci with a sex-specific effect; one on Chr 5 with a maximum lod score of 7.3 in males and the other on Chr 7 with a maximum lod score of 3.2 in females. Of particular interest is the Chr 5-QTL, because it co-localizes almost perfectly with the recently reported QTL for vulnerability to stroke in the SHRSP (Nature Genet, 16:364-7, 1997). In humans, several epidemiological evidences have suggested the “J-shaped” correlation between serum cholesterol levels and incidence of stroke. Our finding of the co-localization of the QTLs for cholesterol levels and a stroke-associated phenotype in the SHRSP may therefore provide a unique clue to the investigation of the genetical and pathophysiological bases of human stroke.