A genome-wide association study identifies new loci for ACE activity: potential implications for response to ACE inhibitor

• Published in: The pharmacogenomics journal Vol. 10; no. 6; pp. 537 - 544
• Main Authors: Chung, C-M, Wang, R-Y, Chen, J-W, Fann, C S J, Leu, H-B, Ho, H-Y, Ting, C-T, Lin, T-H, Sheu, S-H, Tsai, W-C, Chen, J-H, Jong, Y-S, Lin, S-J, Chen, Y-T, Pan, W-H
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2010; Nature Publishing Group
• Subjects: 631/208/205/2138; 692/699/75/243; 692/700/565/1436/434; ABO Blood-Group System - genetics; ABO system; ACE inhibitors; ACE protein; Adult; Angiotensin; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Angiotensin-Converting Enzyme Inhibitors - therapeutic use; Biomedical and Life Sciences; Biomedicine; Blood pressure; Blood Pressure - genetics; Drug therapy; Female; Gene deletion; Gene Expression; Gene polymorphism; Genetic aspects; Genome-wide association studies; Genome-Wide Association Study; Genomes; Health aspects; Human Genetics; Humans; Hypertension; Hypertension - drug therapy; Hypertension - genetics; Insertion; Male; Oncology; original-article; Peptidyl-dipeptidase A; Peptidyl-Dipeptidase A - blood; Peptidyl-Dipeptidase A - genetics; Pharmacogenetics; Pharmacotherapy; Polymorphism, Single Nucleotide; Psychopharmacology; Quantitative genetics; Quantitative Trait Loci; Single-nucleotide polymorphism; Taiwan; hypertension; pharmacogenetics; GWAS
• ISSN: 1470-269X; 1473-1150
• DOI: 10.1038/tpj.2009.70

Because angiotensin-converting enzyme (ACE) activity is implicated widely in biological systems, we aimed to identify its novel quantitative trait loci for the purposes of understanding ACE activity regulation and pharmacogenetics relating to ACE inhibitor (ACEI). We performed a two-stage genome-wide association study: (1) from 400 young-onset hypertension (YOH) subjects and (2) a confirmation study with an additional 623 YOH subjects. In the first stage, eight single nucleotide polymorphisms (SNPs) of the ACE structural gene and one SNP of ABO genes were significantly associated with ACE activity. SNP rs4343 in exon17 near the well-known insertion/deletion polymorphism had the strongest association. We confirmed in the second stage that three SNPs: rs4343 in ACE gene ( P =3.0 × 10 −25 ), rs495828 ( P =3.5 × 10 −8 ) and rs8176746 ( P =9.3 × 10 −5 ) in ABO gene were significantly associated with ACE activity. We further replicated the association between ABO genotype/blood types and ACE activity in an independent YOH family study (428 hypertension pedigrees), and showed a potential differential blood pressure response to ACEI in subjects with varied numbers of ACE-activity-raising alleles. These findings may broaden our understanding of the mechanisms controlling ACE activity and advance our pharmacogenetic knowledge on ACEI.