Haplotype association analysis of AGT variants with hypertension-related traits: the HyperGEN study.
OBJECTIVE
Function of the renin-angiotensin system is important to human hypertension, but its genetic etiology remains elusive. We set out to examine a hypothesis that multiple genetic variants in the system act together in blood pressure regulation, via intermediate phenotypes such as blood pressure reactivity.


METHODS
A sample of 531 hypertensive cases and 417 controls was selected from the HyperGEN study. Hypertension-related traits including blood pressure responses to challenges to math test, handgrip and postural change (mathBP, gripBP, and postBP), and body mass index (BMI) were analyzed for association with 10 single nucleotide polymorphisms (SNPs) in the angiotensinogen (AGT) gene. Single-marker and haplotype analyses were performed to examine the effects of both individual and multiple variants. Multiple-trait profiling was used to assess interaction of latent intermediate factors with susceptible haplotypes.


RESULTS
In Blacks, two SNPs in exon 5 and 3'UTR showed significant association with gripBP, and two promoter SNPs were strongly associated with postBP. In Whites, only borderline association was found for 2 promoter SNPs with mathBP. Haplotype analyses in Blacks confirmed association with gripBP, and detected significant association of a haplotype to BMI (p=0.029). With the interactions modeled, haplotype associations found in Blacks remain significant, while significant associations to BMI (p=0.009) and gripSBP emerged in Whites.


CONCLUSIONS
Genetic variants in regulatory regions of AGT showed strong association with blood pressure reactivity. Interaction of promoter and genic SNPs in AGT revealed collective action of multiple variants on blood pressure reactivity and BMI both in Blacks and in Whites, possibly following different pathways.
Gu
C Charles
CC
Division of Biostatistics, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA. gc@wubios.wustl.edu
Chang
Yen-Pei C
YP
Hunt
Steven C
SC
Schwander
Karen
K
Arnett
Donna
D
Djousse
Luc
L
Heiss
Gerardo
G
Oberman
Al
A
Lalouel
Jean-Marc
JM
Province
Mike
M
Chakravarti
Aravinda
A
Rao
D C
DC
D001741:Black or African American / Q000235:genetics; D000704:Analysis of Variance; D000808:Angiotensinogen / Q000235:genetics*; D001794:Blood Pressure / Q000235:genetics / Q000502:physiology; D015992:Body Mass Index; D016000:Cluster Analysis; D005260:Female; D014644:Genetic Variation; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D006973:Hypertension / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D044465:White People / Q000235:genetics
D000808:Angiotensinogen