Combination of multiple genetic risk factors is synergistically associated with carotid atherosclerosis in Japanese subjects with type 2 diabetes.
OBJECTIVE
Several genetic risk factors, such as single nucleotide polymorphisms (SNPs), in candidate genes have been reported to be responsible for intima-media thickness (IMT), which is one of the surrogate end points of cardiovascular events. However, the synergistic effects of SNPs have not been evaluated in detail.


METHODS
We measured the average IMT of the common and internal carotid artery in Japanese type 2 diabetic patients (n = 690) (>50 years old) using ultrasonography. We also determined their genotypes regarding 106 SNPs in candidate genes responsible for cardiovascular diseases. Among the 106 SNPs, we selected 40 common (frequency of minor allele >/=10%) SNPs. We compared the average IMT of subjects with and without any pairs of four genotypes selected from the 40 common SNPs.


RESULTS
The combination of methylen-tetrahydrofolate reductase 677 TT genotype and lymphotoxin-alpha (LTA) 252 GG genotype and that of ACE DD genotype and LTA 252 GG genotype were evaluated as responsible for a statistically significant (P = 2.7 x 10(-9) and 3.5 x 10(-6), respectively) increase in average IMT (mean [+/-SD] 1.54 +/- 0.60 and 1.43 +/- 0.58 mm, respectively) compared with those of the subjects without these combinations (1.04 +/- 0.34 and 1.04 +/- 0.34 mm, respectively). No single genotype was shown to be responsible for the statistically significant difference in average IMT after Bonferroni's multiple comparison procedure.


CONCLUSIONS
The present analysis demonstrates an approach to evaluate combinations of multiple genetic risk factors that are synergistically associated with carotid atherosclerosis.
Yamasaki
Yoshimitsu
Y
Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita City, Osaka 565-0871, Japan. yamasaki@medone.med.osaka-u.ac.jp
Katakami
Naoto
N
Sakamoto
Ken'ya
K
Kaneto
Hideaki
H
Matsuhisa
Munehide
M
Sato
Hiroshi
H
Hori
Masatsugu
M
Haneda
Masakazu
M
Kashiwagi
Atsunori
A
Tanaka
Yasushi
Y
Kawamori
Ryuzo
R
Kuno
Shin-Ichi
S
D000368:Aged; D002340:Carotid Artery Diseases / Q000000981:diagnostic imaging / Q000208:ethnology* / Q000235:genetics*; D017536:Carotid Artery, Common / Q000000981:diagnostic imaging; D002343:Carotid Artery, Internal / Q000000981:diagnostic imaging; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000208:ethnology* / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D005838:Genotype; D006801:Humans; D007564:Japan / Q000453:epidemiology; D008233:Lymphotoxin-alpha / Q000235:genetics; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D017539:Tunica Intima / Q000000981:diagnostic imaging; D017540:Tunica Media / Q000000981:diagnostic imaging; D014463:Ultrasonography
D008233:Lymphotoxin-alpha; D042965:Methylenetetrahydrofolate Reductase (NADPH2)