Association of three-gene interaction among MTHFR, ALOX5AP and NOTCH3 with thrombotic stroke: a multicenter case–control study
- 366 Downloads
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.
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.
- Chen Z, Karaplis AC, Ackerman SL, Pogribny IP, Melnyk S, Lussier-Cacan S et al (2001) Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition. Hum Mol Genet 10(5):433–443PubMedCrossRefGoogle Scholar
- Li Z, Sun L, Zhang H, Liao Y, Wang D, Zhao B et al (2003) Elevated plasma homocysteine was associated with hemorrhagic and ischemic stroke, but methylenetetrahydrofolate reductase gene C677T variant was a risk factor for thrombotic stroke: a multicenter case–control study in China. Stroke 34(9):2085–2090PubMedCrossRefGoogle Scholar
- Moore JH, Gilbert JC, Tsai CT, Chiang FT, Holden T, Barney N, White BC (2006) A flexible computational framework for detecting, characterizing, and interpreting statistical patterns of epistasis in genetic studies of human disease susceptibility. J Theor Biol 241(2):252–261PubMedCrossRefGoogle Scholar
- Sun L, Li Z, Zhang H, Ma A, Liao Y, Wang D et al (2003) Pentanucleotide TTTTA repeat variant of apolipoprotein(a) gene and plasma lipoprotein(a) are associated with ischemic and hemorrhagic stroke in Chinese: a multicenter case–control study in China. Stroke 34(7):1617–1622PubMedCrossRefGoogle Scholar
- World Health Organization (2003) The World Health Report 2003: shaping the future. World Health Organization, GenevaGoogle Scholar