The association between the -374T/A polymorphism of the receptor for advanced glycation endproducts gene and blood pressure and arterial stiffness is modified by glucose metabolism status: the Hoorn and CoDAM studies.
OBJECTIVE
Receptor for advanced glycation endproducts (RAGE)-ligand interaction may lead to vascular complications. Genetic variation in RAGE has been shown to alter expression, activity of RAGE or both. We, therefore, investigated whether RAGE single-nucleotide polymorphisms (SNPs) and haplotypes were associated with vascular disease.


METHODS
Nine tag SNPs that cover the common RAGE gene variation were genotyped in 1291 individuals from two Dutch population-based cohort studies, aged 64.5 +/- 8.6 years, with normal glucose metabolism (44%), impaired glucose metabolism (23%) or type 2 diabetes mellitus (33%). We used multiple regression analyses to compare prevalent cardiovascular disease and markers of atherosclerosis, blood pressure and arterial stiffness across genotypes, and examine effect modification by glucose metabolism status.


RESULTS
In unstratified analyses, no consistent associations between RAGE SNPs and prevalent cardiovascular disease and markers of atherosclerosis were found. However, the AA genotype of SNP rs1800624 (-374T/A) was consistently associated with lower SBP [-5.0 mmHg (95% confidence interval -10.4 to 0.3)] and DBP [-4.2 (-7.2 to -1.3)], pulse pressure [-0.8 (-5.0 to 3.4)] as well as with less arterial stiffness [-0.56 SD (-1.04 to -0.09)] in individuals with normal glucose metabolism, but with higher SBP [6.2 (0.9-11.5)], DBP [2.1 (-0.7 to 5.0)] and pulse pressure [4.1 (-0.2 to 8.4)] in individuals with impaired glucose metabolism or type 2 diabetes mellitus (P for interaction <or=0.05 in all analyses). Similar results were found for a haplotype that includes the -374A allele.


CONCLUSIONS
In individuals with normal glucose metabolism, the -374A allele of the RAGE gene is protectively associated with blood pressure and arterial stiffness, whereas in individuals with impaired glucose metabolism or type 2 diabetes mellitus, it is adversely associated with these variables.
Engelen
Lian
L
Cardiovascular Research Institute Maastricht (CARIM), The Netherlands.
Ferreira
Isabel
I
Gaens
Katrien H J
KH
Henry
Ronald M A
RM
Dekker
Jacqueline M
JM
Nijpels
Giel
G
Heine
Robert J
RJ
't Hart
Leen M
LM
van Greevenbroek
Marleen M J
MM
van der Kallen
Carla J H
CJ
Blaak
Ellen E
EE
Feskens
Edith J M
EJ
Ten Cate
Hugo
H
Stehouwer
Coen D A
CD
Schalkwijk
Casper G
CG
D000368:Aged; D050197:Atherosclerosis / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D001483:Base Sequence; D001794:Blood Pressure / Q000235:genetics*; D002318:Cardiovascular Diseases / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D015331:Cohort Studies; D017931:DNA Primers / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000503:physiopathology; D005260:Female; D005947:Glucose / Q000378:metabolism*; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D020641:Polymorphism, Single Nucleotide; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics*; D012307:Risk Factors; D014655:Vascular Resistance / Q000235:genetics*
D017931:DNA Primers; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D005947:Glucose