Association of three-gene interaction among MTHFR, ALOX5AP and NOTCH3 with thrombotic stroke: a multicenter case-control study.
Stroke is a common complex trait and does not follow Mendelian pattern of inheritance. Gene-gene or gene-environment interactions may be responsible for the complex trait. How the interactions contribute to stroke is still under research. This study aimed to explore the association between gene-gene interactions and stroke in Chinese in a large case-control study. Nearly 4,000 participants were recruited from seven clinical centers. Eight variants in five candidate genes were examined for stroke risk. Gene-gene interactions were explored by using Generalized Multifactor Dimensionality Reduction (GMDR). A significant gene-gene interaction was found by GMDR. The best model including MTHFR C677T, ALOX5AP T2354A and NOTCH3 C381T scored 10 for Cross-Validation Consistency and 9 for Sign Test (P = 0.0107). The individuals with combination of MTHFR 677TT, ALOX5AP 2354AA and NOTCH3 381TT/TC had a significantly higher risk of thrombotic stroke (OR 3.165, 95% CI 1.461-6.858, P = 0.003). Our results show that combination of these alleles conferred higher risk for stroke than single risk allele. The gene-gene interaction may serve as a novel area for stroke research. The three-locus combination may change the susceptibility of particular subjects to the disease.
Sino-German Laboratory, Molecular Medicine, Key Laboratory for Clinical Cardiovascular Genetics of Ministry of Education, FuWai Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China. ljh.bb.bj@gmail.com
Junhao
J
Liu
Kai
K
Sun
Yongyi
Y
Bai
Weili
W
Zhang
Xiaojian
X
Wang
Yibo
Y
Wang
Hu
H
Wang
Jingzhou
J
Chen
Xiaodong
X
Song
Ying
Y
Xin
Zhe
Z
Liu
Rutai
R
Hui
D058927:5-Lipoxygenase-Activating Proteins; D000368:Aged; D000483:Alleles; D044466:Asian People / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D020767:Intracranial Thrombosis / Q000235:genetics*; D016015:Logistic Models; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D008957:Models, Genetic; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics*; D012307:Risk Factors; D020521:Stroke / Q000235:genetics*
D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; D002352:Carrier Proteins; D008565:Membrane Proteins; C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D042965:Methylenetetrahydrofolate Reductase (NADPH2)