The apolipoprotein A-IV Gln360His polymorphism predicts progression of coronary artery calcification in patients with type 1 diabetes.
OBJECTIVE
Individuals with type 1 diabetes have an increased incidence of coronary artery disease (CAD) and a higher risk of cardiovascular death compared with individuals of the same age in the general population. While chronic hyperglycaemia and insulin resistance partially explain excess CAD, little is known about the potential genetic determinants of accelerated coronary atherosclerosis in type 1 diabetes. The aim of the present study was to evaluate the association of apolipoprotein A-IV (APOA4) polymorphisms with coronary artery calcification (CAC) progression, a marker of subclinical atherosclerosis.


METHODS
Two previously well-studied functional APOA4 polymorphisms resulting in the substitution of the amino acid Thr for Ser at codon 347 and Gln for His at codon 360 were genotyped in 634 subjects with type 1 diabetes and 739 non-diabetic control subjects, the participants of the prospective Coronary Artery Calcification in Type 1 Diabetes (CACTI) study.


RESULTS
The His360 allele was associated with a significantly higher risk of CAC progression among patients with type 1 diabetes (33.7 vs 21.2%, p=0.014), but not in the control subjects (14.1 vs 11.1%, p=0.42). Logistic regression analysis confirmed that the presence of the APOA4 His360 allele predicts an increased risk of progression of coronary atherosclerosis in adults with type 1 diabetes of long duration (odds ratio = 3.3, p=0.003 after adjustment for covariates associated with CAD risk). CONCLUSIONS /INTERPRETATION: This is the first report suggesting an association between the APOA4 Gln360His polymorphism and risk of CAC progression in subjects with type 1 diabetes. Additional studies are needed to explore potential interactions between APOA4 genotypes and metabolic/oxidative stress components of the diabetic milieu leading to rapid progression of atherosclerosis.
Kretowski
A
A
Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Mail Stop A140, P.O. Box 6511, Aurora, CO 80045-6511, USA. Adam.Kretowski@UCHSC.edu
Hokanson
J E
JE
McFann
K
K
Kinney
G L
GL
Snell-Bergeon
J K
JK
Maahs
D M
DM
Wadwa
R P
RP
Eckel
R H
RH
Ogden
L G
LG
Garg
S K
SK
Li
J
J
Cheng
S
S
Erlich
H A
HA
Rewers
M
M
D000328:Adult; D019943:Amino Acid Substitution; D001054:Apolipoproteins A / Q000235:genetics*; D015331:Cohort Studies; D003324:Coronary Artery Disease / Q000235:genetics*; D004247:DNA / Q000097:blood / Q000235:genetics / Q000302:isolation & purification; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D003925:Diabetic Angiopathies / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D011110:Polymorphism, Genetic; D012016:Reference Values
D001054:Apolipoproteins A; C022205:apolipoprotein A-IV; D004247:DNA