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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.

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This research was supported by Ministry of Science and Technology of China (2006DFA31500 and 2007DFC30340 to Dr. Hui). We greatly appreciate Dr. Ming Li and his colleagues, working at the Departments of Psychiatry and Neurobehavioral Sciences and Public Health Sciences, University of Virginia, Charlottesville, for making their GMDR Java software available for this project. We also thank Dr. Jason H. Moore of Computational Genetics Laboratory, Dartmouth Medical School, Hanover, NH, for his advices on MDR application.

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Correspondence to Rutai Hui.

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Liu, J., Sun, K., Bai, Y. et al. Association of three-gene interaction among MTHFR, ALOX5AP and NOTCH3 with thrombotic stroke: a multicenter case–control study. Hum Genet 125, 649–656 (2009).

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  • Stroke Risk
  • Multifactor Dimensionality Reduction
  • MTHFR C677T
  • Lacunar Infarction
  • Plasma Homocysteine Concentration