Genetic determinants of metabolic syndrome components in the stroke-prone spontaneously hypertensive rat.
OBJECTIVE
The metabolic syndrome is a complex multifactorial disease, which results from interactions between genes on multiple chromosomes and environmental factors. Animal models may facilitate genetic analysis of complex phenotypes by allowing complete control of environmental conditions and the ability to produce designer strains.


METHODS
Stroke-prone spontaneously hypertensive (SHRSP) and Wistar-Kyoto (WKY) rat strains were used to construct congenic (SP.WKYGla2a), consomic (SP.WKYGlaYw, WKY.SPGlaYs) and double-introgressed (SP.WKYGla2aYw) strains, which were characterized for metabolic syndrome phenotypes (systolic blood pressure, glucose tolerance and lipid profile) after feeding a 60% fructose diet for 14 days.


RESULTS
The Y consomic strain (SP.WKYGlaYw) demonstrated that the WKY Y chromosome significantly lowered triglyceride levels (3.77 +/- 0.60 versus 9.09 +/- 1.47 mmol/l; P < 0.001) and improved glucose tolerance [area under the curve (AUC): 26.93 +/- 0.81 versus 31.47 +/- 0.89; P < 0.05] compared with SHRSP. The chromosome 2 congenic strain (SP.WKYGla2a) exhibited significantly improved glucose tolerance (AUC: 28.19 +/- 1.17 versus 31.47 +/- 0.89; P < 0.05) and lower systolic blood pressure (161.2 +/- 6.2 versus 179.7 +/- 3.9 mmHg; P < 0.05) compared with SHRSP. 2 x 2 factorial ANOVA identified a significant interaction for glucose metabolism (P = 0.004) in the double-introgressed strain (SP.WKYGla2aYw) between chromosome 2 and Y.


CONCLUSIONS
These results identify novel interacting regions on chromosome 2 and the Y chromosome influencing a cluster of metabolic and cardiovascular phenotypes. Translation to clinical studies will facilitate genetic dissection of human metabolic syndrome.
Strahorn
Pamela
P
BHF Glasgow Cardiovascular Research Centre, Division of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
Graham
Delyth
D
Charchar
Fadi J
FJ
Sattar
Naveed
N
McBride
Martin W
MW
Dominiczak
Anna F
AF
D000818:Animals; D020296:Animals, Congenic; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000235:genetics; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D005260:Female; D005632:Fructose / Q000008:administration & dosage; D005951:Glucose Tolerance Test; D006801:Humans; D006973:Hypertension / Q000235:genetics; D008297:Male; D024821:Metabolic Syndrome / Q000097:blood / Q000235:genetics*; D010641:Phenotype; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D020521:Stroke / Q000235:genetics; D014280:Triglycerides / Q000097:blood; D014998:Y Chromosome / Q000235:genetics
D001786:Blood Glucose; D014280:Triglycerides; D005632:Fructose