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.

Figure 1. Mapping of a systolic blood pressure (SBP) quantitative trait locus (QTL) in BXD strains.

(A) Rank ordered mean BP values across 27 male and 21 female BXD strains (with SEM error bars). (B) In males, a significant BP QTL is mapped on chromosome 9. In females, BP QTL maps to the same region on chromosome 9. (C) The genomic region corresponding to the BP QTL on chromosome 9. The LOD score is depicted in blue with the highest values at the position 113.2 to 113.9 Mb achieving LOD of 4.7. Individual genes under the BP QTL peak are indicated. (D) The syntenic chromosomal region in human.

Figure 2. Regional association plots of the genomic location indicated by the mouse model in the EUGENE2 human study population.

Associations of SNPs rs17030583 and rs2291897 (blue diamonds) to systolic and diastolic blood pressure are plotted with their P-values (as −log10 values) as a function of genomic position (with NCBI build 36). Estimated recombination rates (from Hapmap Phase 3) are plotted to reflect the local LD structure around the associated SNPs and their correlated proxies (red: r²≥0.8; orange: 0.5≤r²<0.8; gray: 0.2≤r²<0.5; white: r²<0.2). Diamonds represent directly genotyped markers and circles represent imputed markers.

Figure 3. Gene and LD block structure of the human chromosome 3. 33.2–33.9 Mb region.

Based on the imputed EUGENE2 data. Dark red color represents perfect LD (R²) of 1 between the markers.