title: Combination of multiple genetic risk factors is synergistically associated with carotid atherosclerosis in Japanese subjects with type 2 diabetes.
abstract: 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.
authors.affiliation: 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
authors.forename: Yoshimitsu
authors.initials: Y
authors.lastname: Yamasaki
authors.forename: Naoto
authors.initials: N
authors.lastname: Katakami
authors.forename: Ken'ya
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kaneto
authors.forename: Munehide
authors.initials: M
authors.lastname: Matsuhisa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sato
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Hori
authors.forename: Masakazu
authors.initials: M
authors.lastname: Haneda
authors.forename: Atsunori
authors.initials: A
authors.lastname: Kashiwagi
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Ryuzo
authors.initials: R
authors.lastname: Kawamori
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Kuno
mesh_terms: 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
chemical_list: D008233:Lymphotoxin-alpha; D042965:Methylenetetrahydrofolate Reductase (NADPH2)