Human Genetics

, Volume 125, Issue 5–6, pp 649–656 | Cite as

Association of three-gene interaction among MTHFR, ALOX5AP and NOTCH3 with thrombotic stroke: a multicenter case–control study

  • Junhao Liu
  • Kai Sun
  • Yongyi Bai
  • Weili Zhang
  • Xiaojian Wang
  • Yibo Wang
  • Hu Wang
  • Jingzhou Chen
  • Xiaodong Song
  • Ying Xin
  • Zhe Liu
  • Rutai Hui
Original Investigation

Abstract

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.

Notes

Acknowledgments

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.

Supplementary material

439_2009_659_MOESM1_ESM.doc (77 kb)
Frequency of Each Polymorphism (DOC 77 kb)
439_2009_659_MOESM2_ESM.doc (46 kb)
Frequency of seven unlinked microsatellite markers (DOC 46 kb)

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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Junhao Liu
    • 1
  • Kai Sun
    • 1
  • Yongyi Bai
    • 1
  • Weili Zhang
    • 1
  • Xiaojian Wang
    • 1
  • Yibo Wang
    • 1
  • Hu Wang
    • 1
  • Jingzhou Chen
    • 1
  • Xiaodong Song
    • 1
  • Ying Xin
    • 1
  • Zhe Liu
    • 1
  • Rutai Hui
    • 1
  1. 1.Sino-German Laboratory, Molecular Medicine, Key Laboratory for Clinical Cardiovascular Genetics of Ministry of Education, FuWai HospitalChinese Academy of Medical Sciences, Peking Union Medical CollegeBeijingChina

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