A genome-wide association study identifies new loci for ACE activity: potential implications for response to ACE inhibitor.
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 x 10⁻²⁵), rs495828 (P=3.5 x 10⁻⁸) and rs8176746 (P=9.3 x 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.
Chung
C-M
CM
Division of Molecular Medicine, Institute of Public Health, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
Wang
R-Y
RY
Chen
J-W
JW
Fann
C S J
CS
Leu
H-B
HB
Ho
H-Y
HY
Ting
C-T
CT
Lin
T-H
TH
Sheu
S-H
SH
Tsai
W-C
WC
Chen
J-H
JH
Jong
Y-S
YS
Lin
S-J
SJ
Chen
Y-T
YT
Pan
W-H
WH
D000017:ABO Blood-Group System / Q000235:genetics; D000328:Adult; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D001794:Blood Pressure / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000097:blood / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci
D000017:ABO Blood-Group System; D000806:Angiotensin-Converting Enzyme Inhibitors; D007703:Peptidyl-Dipeptidase A