title: Identification of the UBP1 locus as a critical blood pressure determinant using a combination of mouse and human genetics.
abstract: Hypertension is a major health problem of largely unknown genetic origins. To identify new genes responsible for hypertension, genetic analysis of recombinant inbred strains of mice followed by human association studies might prove powerful and was exploited in our current study. Using a set of 27 recombinant BXD strains of mice we identified a quantitative trait locus (QTL) for blood pressure (BP) on distal chromosome 9. The association analysis of markers encompassing the syntenic region on human chromosome 3 gave in an additive genetic model the strongest association for rs17030583 C/T and rs2291897 G/A, located within the UBP1 locus, with systolic and diastolic BP (rs17030583: 1.3+/-0.4 mmHg p<0.001, 0.8+/-0.3 mmHg p = 0.006, respectively and rs2291897: 1.5+/-0.4 mmHg p<0.001, 0.8+/-0.3 mmHg p = 0.003, respectively) in three separate studies. Our study, which underscores the marked complementarities of mouse and human genetic approaches, identifies the UBP1 locus as a critical blood pressure determinant. UBP1 plays a role in cholesterol and steroid metabolism via the transcriptional activation of CYP11A, the rate-limiting enzyme in pregnenolone and aldosterone biosynthesis. We suggest that UBP1 and its functional partners are components of a network controlling blood pressure.
authors: Institut Clinique de la Souris, Illkirch, France.
authors: Hana
authors: H
authors: Koutnikova
authors: Markku
authors: M
authors: Laakso
authors: Lu
authors: L
authors: Lu
authors: Roy
authors: R
authors: Combe
authors: Jussi
authors: J
authors: Paananen
authors: Teemu
authors: T
authors: Kuulasmaa
authors: Johanna
authors: J
authors: Kuusisto
authors: Hans-Ulrich
authors: HU
authors: Häring
authors: Torben
authors: T
authors: Hansen
authors: Oluf
authors: O
authors: Pedersen
authors: Ulf
authors: U
authors: Smith
authors: Markolf
authors: M
authors: Hanefeld
authors: Robert W
authors: RW
authors: Williams
authors: Johan
authors: J
authors: Auwerx
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001794:Blood Pressure; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008875:Middle Aged; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D014157:Transcription Factors; C085968:UBP1 protein, human; C094751:Ubp1 protein, mouse