Haplotype of the angiotensinogen gene is associated with coronary heart disease in familial hypercholesterolemia.
OBJECTIVE
Familial hypercholesterolemia is characterized by high plasma low-density lipoprotein cholesterol levels and premature coronary heart disease. Despite the monogenetic origin of familial hypercholesterolemia, the incidence of coronary heart disease varies considerably among patients, which is only partly explained by classical risk factors. Hypertension is an important risk factor for coronary heart disease that is associated with angiotensinogen levels. Therefore, we analyzed the angiotensinogen gene as a modifier gene for coronary heart disease risk in patients with familial hypercholesterolemia.


METHODS
In a cohort of 1785 familial hypercholesterolemia patients, we reconstructed five frequent haplotypes of the angiotensinogen gene, based on four polymorphisms. The five haplotypes cover approximately 98% of the genetic diversity accounted for by these four polymorphisms. The associations between the haplotypes and coronary heart disease were analyzed with the haplo.stats program, adjusted for age, sex and smoking.


RESULTS
Patients homozygous for the C allele of the 4072 T>C polymorphism had a 34% increased coronary heart disease risk (P = 0.017) compared to patients homozygous for the T allele. Haplotype H3, consisting of the minor allele of the 4072T>C polymorphism and the major alleles of the other polymorphisms, had a frequency of 15% and was associated with a 45% increased coronary heart disease risk (P = 0.006) compared to the wild-type haplotype H1.


CONCLUSIONS
We conclude that genetic variation in the angiotensinogen gene contributes to coronary heart disease risk in patients with familial hypercholesterolemia.
van der Net
Jeroen B
JB
Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
Isaacs
Aaron
A
Dallinga-Thie
Geesje M
GM
Kastelein
John Jp
JJ
Defesche
Joep C
JC
Steyerberg
Ewout W
EW
Sijbrands
Eric Jg
EJ
D000328:Adult; D000483:Alleles; D000808:Angiotensinogen / Q000235:genetics*; D003324:Coronary Artery Disease / Q000235:genetics*; D005260:Female; D006239:Haplotypes; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic
D000808:Angiotensinogen