High-resolution mapping of a novel rat blood pressure locus on chromosome 9 to a region containing the Spp2 gene and colocalization of a QTL for bone mass.
Through linkage analysis of the Dahl salt-sensitive (S) rat and the spontaneously hypertensive rat (SHR), a blood pressure (BP) quantitative trait locus (QTL) was previously located on rat chromosome 9. Subsequent substitution mapping studies of this QTL revealed multiple BP QTLs within the originally identified logarithm of odds plot by linkage analysis. The focus of this study was on a 14.39 Mb region, the distal portion of which remained unmapped in our previous studies. High-resolution substitution mapping for a BP QTL in the setting of a high-salt diet indicated that an SHR-derived congenic segment of 787.9 kb containing the gene secreted phosphoprotein-2 (Spp2) lowered BP and urinary protein excretion. A nonsynonymous G/T polymorphism in the Spp2 gene was detected between the S and S.SHR congenic rats. A survey of 45 strains showed that the T allele was rare, being detected only in some substrains of SHR and WKY. Protein modeling prediction through SWISSPROT indicated that the predicted protein product of this variant was significantly altered. Importantly, in addition to improved cardiovascular and renal function, high salt-fed congenic animals carrying the SHR T variant of Spp2 had significantly lower bone mass and altered bone microarchitecture. Total bone volume and volume of trabecular bone, cortical thickness, and degree of mineralization of cortical bone were all significantly reduced in congenic rats. Our study points to opposing effects of a congenic segment containing the prioritized candidate gene Spp2 on BP and bone mass.
Program in Physiological Genomics, Center for Hypertension and Personalized Medicine, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio;
Ying
Y
Nie
Program in Physiological Genomics, Center for Hypertension and Personalized Medicine, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio;
Sivarajan
S
Kumarasamy
Program in Physiological Genomics, Center for Hypertension and Personalized Medicine, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio;
Harshal
H
Waghulde
Program in Physiological Genomics, Center for Hypertension and Personalized Medicine, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio;
Xi
X
Cheng
Program in Physiological Genomics, Center for Hypertension and Personalized Medicine, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio;
Blair
B
Mell
Center for Diabetes and Endocrine Research, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio; and Department of Orthopedics, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio.
Piotr J
PJ
Czernik
Center for Diabetes and Endocrine Research, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio; and Department of Orthopedics, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio.
Beata
B
Lecka-Czernik
Program in Physiological Genomics, Center for Hypertension and Personalized Medicine, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio; bina.joe@utoledo.edu.
Bina
B
Joe
D000483:Alleles; D000818:Animals; D020296:Animals, Congenic / Q000235:genetics; D001794:Blood Pressure / Q000235:genetics*; D001842:Bone and Bones / Q000378:metabolism*; D002874:Chromosome Mapping / Q000379:methods; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D008040:Genetic Linkage / Q000235:genetics; D006801:Humans; D006973:Hypertension / Q000235:genetics; D008297:Male; D010750:Phosphoproteins / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics*; D051381:Rats; D020303:Rats, Inbred Dahl; D011918:Rats, Inbred SHR / Q000235:genetics; D011921:Rats, Inbred WKY; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage
D010750:Phosphoproteins; D017673:Sodium Chloride, Dietary
S; bone density; congenic strains; human chromosome 2; hypertension; skeletal