Are "functionally related polymorphisms" of renin-angiotensin-aldosterone system gene polymorphisms associated with hypertension?
BACKGROUND
Genotype-phenotype association studies are typically based upon polymorphisms or haplotypes comprised of multiple polymorphisms within a single gene. It has been proposed that combinations of polymorphisms in distinct genes, which functionally impact the same phenotype, may have stronger phenotype associations than those within a single gene. We have tested this hypothesis using genes encoding components of the renin-angiotensin-aldosterone system and the high blood pressure phenotype.


METHODS
Our analysis is based on 1379 participants of the cross-sectional SUNSET study randomly selected from the population register of Amsterdam. Each subject was genotyped for the angiotensinogen M235T, the angiotensin-converting enzyme insertion/deletion and the angiotensin II type 1 receptor A1166C polymorphism. The phenotype high blood pressure was defined either as a categorical variable comparing hypertension versus normotension as in most previous studies or as a continuous variable using systolic, diastolic and mean blood pressure in a multiple regression analysis with gender, ethnicity, age, body-mass-index and antihypertensive medication as covariates.


RESULTS
Genotype-phenotype relationships were explored for each polymorphism in isolation and for double and triple polymorphism combinations. At the single polymorphism level, only the A allele of the angiotensin II type 1 receptor was associated with a high blood pressure phenotype. Using combinations of polymorphisms of two or all three genes did not yield stronger/more consistent associations.


CONCLUSIONS
We conclude that combinations of physiologically related polymorphisms of multiple genes, at least with regard to the renin-angiotensin-aldosterone system and the hypertensive phenotype, do not necessarily offer additional benefit in analyzing genotype/phenotype associations.
Dept. of Pharmacology & Pharmacotherapy, Academic Medical Center, University of Amsterdam, The Netherlands.
Ines N
IN
Hahntow
Gideon
G
Mairuhu
Irene Gm
IG
van Valkengoed
Richard P
RP
Koopmans
Martin C
MC
Michel
D000328:Adult; D000808:Angiotensinogen / Q000235:genetics; D001795:Blood Pressure Determination; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D006973:Hypertension / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D011110:Polymorphism, Genetic; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics*; D012083:Renin / Q000235:genetics; D012084:Renin-Angiotensin System / Q000235:genetics; D012307:Risk Factors
D044140:Receptor, Angiotensin, Type 1; D000808:Angiotensinogen; D012083:Renin