Genome-Wide and Gene-Based Meta-Analyses Identify Novel Loci Influencing Blood Pressure Response to Hydrochlorothiazide

This study aimed to identify novel loci influencing the antihypertensive response to hydrochlorothiazide monotherapy. A genome-wide meta-analysis of blood pressure (BP) response to hydrochlorothiazide was performed in 1739 white hypertensives from 6 clinical trials within the International Consortium for Antihypertensive Pharmacogenomics Studies, making it the largest study to date of its kind. No signals reached genome-wide significance (P<5×10−8), and the suggestive regions (P<10−5) were cross-validated in 2 black cohorts treated with hydrochlorothiazide. In addition, a gene-based analysis was performed on candidate genes with previous evidence of involvement in diuretic response, in BP regulation, or in hypertension susceptibility. Using the genome-wide meta-analysis approach, with validation in blacks, we identified 2 suggestive regulatory regions linked to gap junction protein α1 gene (GJA1) and forkhead box A1 gene (FOXA1), relevant for cardiovascular and kidney function. With the gene-based approach, we identified hydroxy-delta-5-steroid dehydrogenase, 3 β- and steroid δ-isomerase 1 gene (HSD3B1) as significantly associated with BP response (P<2.28×10−4). HSD3B1 encodes the 3β-hydroxysteroid dehydrogenase enzyme and plays a crucial role in the biosynthesis of aldosterone and endogenous ouabain. By amassing all of the available pharmacogenomic studies of BP response to hydrochlorothiazide, and using 2 different analytic approaches, we identified 3 novel loci influencing BP response to hydrochlorothiazide. The gene-based analysis, never before applied to pharmacogenomics of antihypertensive drugs to our knowledge, provided a powerful strategy to identify a locus of interest, which was not identified in the genome-wide meta-analysis because of high allelic heterogeneity. These data pave the way for future investigations on new pathways and drug targets to enhance the current understanding of personalized antihypertensive treatment

Ornithine decarboxylase activity during development of the mouse inner ear in vivo and in vitro

Ornithine decarboxylase activity was determined during the development of the peripheral auditory system in the murine otocyst with the goal of understanding the role of this enzyme in the morphological and functional maturation of the inner ear. At gestational days 11 and 12 enzyme activity was more than 10-fold higher than adult levels. A sharp decline occured between day 12 and 13 after which activity rose to a peak around day 15. Activity then dropped continuously until near-adult levels were reached at birth. A lower specific activity of ODC but a similar time-course was seen in otocysts explanted at gestational day 13 and subsequently cultured for 6 days. For two stages of development, enzyme activity and binding of 3 H-α-difluoromethylornithine were compared. The four-fold difference in enzymatic activity on gestational days 15 and 17 was paralleled by a similar difference in binding. Ornithine decarboxylase activity during inner ear development therefore seems primarily regulated at the level of protein synthesis. Ornithine decarboxylase activity correlates with major inductive events in the morphogenesis of the cartilagenous otic capsule that serves as a template for the formation of the bony labyrinth. The pattern of activity may reflect the changes in the head mesenchyme that is recruited by the otocyst to aggregate and form its protective otic capsule.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47689/1/441_2004_Article_BF00340878.pd

Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease.

Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; ∼75% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A. Further analyses based on common variants suggested that the genome-wide genetic correlation (rG) between PSC and ulcerative colitis (UC) (rG = 0.29) was significantly greater than that between PSC and Crohn's disease (CD) (rG = 0.04) (P = 2.55 × 10-15). UC and CD were genetically more similar to each other (rG = 0.56) than either was to PSC (P < 1.0 × 10-15). Our study represents a substantial advance in understanding of the genetics of PSC