Independent predictive roles of eotaxin Ala23Thr, paraoxonase 2 Ser311Cys and beta-adrenergic receptor Trp64Arg polymorphisms on cardiac disease in Type 2 Diabetes--an 8-year prospective cohort analysis of 1297 patients.
OBJECTIVE
To examine the independent and joint effects of multiple genetic variants on a cardiac end-point in an 8-year prospective study of a Chinese diabetic cohort.


METHODS
Seventy-seven single nucleotide polymorphisms (SNPs) of 53 candidate genes for inflammation, thrombosis, vascular tone regulation and lipid metabolism were genotyped in 1297 Chinese patients with no prior history of coronary heart disease (CHD) or heart failure at baseline. Cardiac end-point was defined by the occurrence of CHD and/or heart failure.


RESULTS
In Cox regression model, after adjustment for baseline confounding variables including age, sex, smoking status, duration of diabetes, glycaemic control, lipid levels, waist circumference, blood pressure, albuminuria and estimated glomerular filtration rate, genetic variants, including Ala/Ala of SCYA11 (eotaxin) Ala23Thr, Cys/Cys or Cys/Ser of PON2 (paraoxonase 2) Ser311Cys and Arg/Arg of ADRB3 (beta3-adrenergic receptor) Trp64Arg, were independently associated with incident cardiac end-point, with respective hazard ratios (95% confidence interval) of 1.70 (1.10-2.61, P=0.037), 1.42 (1.08-1.88, P=0.013) and 3.84 (1.18-12.50, P=0.025). Analysis of the joint effect of the risk alleles showed significant increased risk of the cardiac end-point with increasing number of risk alleles (P<0.001). The adjusted risk for the cardiac end-point was 4.11 (P=0.002) for patients carrying four risk alleles compared with those carrying one or no risk allele.


CONCLUSIONS
The independent risk conferred by genetic variants encoding pathways such as inflammation and lipid metabolism, not adequately reflected by conventional biomarkers, may identify high-risk individuals for intensified control of modifiable risk factors.
Department of Medicine & Therapeutics, The Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.
Y
Y
Wang
A O Y
AO
Luk
R C W
RC
Ma
W Y
WY
So
C H T
CH
Tam
M C Y
MC
Ng
X
X
Yang
L
L
Baum
V
V
Lam
P C Y
PC
Tong
J C N
JC
Chan
D000368:Aged; D043303:Aryldialkylphosphatase / Q000235:genetics*; D054413:Chemokine CCL11 / Q000235:genetics*; D015331:Cohort Studies; D003327:Coronary Disease / Q000150:complications* / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D005260:Female; D005838:Genotype; D006723:Hong Kong; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D022702:Receptors, Adrenergic, beta-3 / Q000235:genetics*; D012044:Regression Analysis
C515456:CCL11 protein, human; D054413:Chemokine CCL11; D022702:Receptors, Adrenergic, beta-3; D043303:Aryldialkylphosphatase