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.
Highlights
Elevated arterial blood pressure is a major health problem accounting for a large proportion of cardiovascular morbidity and mortality world-wide
Using a set of 27 recombinant BXD strains of mice, we identified a quantitative trait locus for blood pressure (BP) on distal chromosome 9 encompassing the UBP1 gene locus
In three subsequent human genetic studies, the syntenic locus was shown to be associated with systolic and diastolic BP, identifying the UBP1 locus as a critical blood pressure determinant
Summary
Elevated arterial blood pressure is a major health problem accounting for a large proportion of cardiovascular morbidity and mortality world-wide. Elevated BP is a major risk factor for the development of cardiovascular disease, including coronary heart disease, congestive heart failure, ischemic and hemorrhagic stroke, renal failure, and peripheral arterial disease [2]. Several genes responsible for rare Mendelian forms of hypertension have been identified (CYP11B1, CYP11B2, HSD11B1, MR, SCNN1B, SCNN1G, WNK1, WNK4) and shown to play a significant role in the renal control of BP [3,4,5,6,7,8,9]. Rare independent mutations in salt handling genes SLC2A3, SLC12A1 and KCNJ1 have been shown to reduce BP and protect from the development of hypertension [10]. Common genetic variants that are associated with BP remain to be identified
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
