Two common haplotypes of the glucocorticoid receptor gene are associated with increased susceptibility to cardiovascular disease in men with familial hypercholesterolemia.
BACKGROUND
Glucocorticoids contribute to the development of atherosclerosis. Four polymorphisms in the glucocorticoid receptor (GR) gene have been reported to alter glucocorticoid sensitivity and have been associated with cardiovascular risk factors. Studies on the relationship between these GR variants and cardiovascular disease (CVD) risk, however, have yielded conflicting results.


OBJECTIVE
We sought to determine whether haplotypes based on functional polymorphisms in the GR gene influenced susceptibility to CVD in a high-risk population.


METHODS
In a multicenter cohort study, 1830 patients with heterozygous familial hypercholesterolemia were genotyped for the functional ER22/23EK, N363S, BclI, and 9beta variants. We analyzed the combined effect of all GR variants by constructing haplotypes and using a Cox proportional hazards regression model with adjustment for year of birth and smoking. The analyses were stratified for sex.


METHODS
The primary outcome measure was CVD defined as coronary, cerebral, and peripheral artery disease.


RESULTS
A total of 359 men (40.8%) and 224 women (23.6%) had a cardiovascular event. In men, the BclI haplotype was associated with a 34% higher CVD risk (confidence interval 1.02-1.76; P = 0.03) and the 9beta haplotype with a 41% higher CVD risk (confidence interval 1.02-1.94; P = 0.04). In women, none of the GR haplotypes was significantly related with CVD. We did not find differences in cardiovascular risk factors between GR haplotypes.


CONCLUSIONS
In this large cohort of high-risk individuals, two common haplotypes in the GR gene modified CVD susceptibility among men.
Koeijvoets
Kristel C M C
KC
Department of Internal Medicine, D-435, Erasmus Medical Center, University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.
van der Net
Jeroen B
JB
van Rossum
Elisabeth F C
EF
Steyerberg
Ewout W
EW
Defesche
Joep C
JC
Kastelein
John J P
JJ
Lamberts
Steven W J
SW
Sijbrands
Eric J G
EJ
D000328:Adult; D000368:Aged; D002318:Cardiovascular Diseases / Q000453:epidemiology* / Q000235:genetics*; D002539:Cerebral Arterial Diseases / Q000453:epidemiology / Q000235:genetics; D003327:Coronary Disease / Q000453:epidemiology / Q000235:genetics; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D023381:Endpoint Determination; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D006937:Hypercholesterolemia / Q000453:epidemiology* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D016016:Proportional Hazards Models; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018570:Risk Assessment; D012907:Smoking / Q000453:epidemiology
D011965:Receptors, Glucocorticoid; D004247:DNA