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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Bonita R, Mendis S, Truelsen T, Bogousslavsky J, Toole J, Yatsu F (2004) The global stroke initiative. Lancet Neurol 3:391–393
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):433–443
Cho YM, Ritchie MD, Moore JH (2004) Multifactor-dimensionality reduction shows a two-locus interaction associated with type 2 diabetes mellitus. Diabetologia 47:549–554
Culverhouse R, Suarez BK, Lin J, Reich T (2002) A perspective on epistasis: limits of models displaying no main effect. Am J Hum Genet 70(2):416–471
De Caterina R, Zampolli A (2004) From asthma to atherosclerosis—5-lipoxygenase, leukotrienes, and inflammation. N Engl J Med 350(1):4–7
Dichgans M (2007) Genetics of ischaemic stroke. Lancet Neurol 6(2):149–161
Dong C, Li WD, Li D, Price RA (2005) Interaction between obesity susceptibility loci in chromosome regions 2p25–p24 and 13q13–q21. Eur J Hum Genet 13:102–108
Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG et al (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10(1):111–113
Hahn LW, Ritchie MD, Moore JH (2003) Multifactor dimensionality reduction software for detecting gene–gene and gene–environment interactions. Bioinformatics 19(3):376–382
Havrda MC, Johnson MJ, O’Neill CF, Liaw L (2006) A novel mechanism of transcriptional repression of p27kip1 through Notch/HRT2 signaling in vascular smooth muscle cells. Thromb Haemost 96(3):361–370
Helgadottir A, Manolescu A, Thorleifsson G, Gretarsdottir S, Jonsdottir H, Thorsteinsdottir U et al (2004) The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nat Genet 36(3):233–239
Helgadottir A, Gretarsdottir S, St Clair D, Manolescu A, Cheung J, Thorleifsson G et al (2005) Association between the gene encoding 5-lipoxygenase-activating protein and stroke replicated in a Scottish population. Am J Hum Genet 76(3):505–509
Hoh J, Ott J (2003) Mathematical multi-locus approaches to localizing complex human trait genes. Nat Rev Genet 4(9):701–709
Hsueh WC, Cole SA, Shuldiner AR, Beamer BA, Blangero J, Hixson JE et al (2001) Interactions between variants in the b3-adrenergic receptor and peroxisome proliferator-activated receptor-g2 genes and obesity. Diabetes Care 24:672–677
Kang SS, Zhou J, Wong PW, Kowalisyn J, Strokosch G (1988) Intermediate homocysteinemia: a thermolabile variant of methylenetetrahydrofolate reductase. Am J Hum Genet 43(4):414–421
Lee JH, Moore JH, Park SW, Jang AS, Uh ST, Kim YH et al (2008) Genetic interactions model among Eotaxin gene polymorphisms in asthma. J Hum Genet 53(10):867–875
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):2085–2090
Liu M, Wu B, Wang WZ, Lee LM, Zhang SH, Kong LZ (2007) Stroke in China: epidemiology, prevention, and management strategies. Lancet Neurol 6(5):456–464
Lou XY, Chen GB, Yan L, Ma JZ, Zhu J, Elston RC et al (2007) A generalized combinatorial approach for detecting gene-by-gene and gene-by-environment interactions with application to nicotine dependence. Am J Hum Genet 80(6):1125–1137
McCully KS (1969) Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol 56:111–126
Moore JH, Williams SM (2002) New strategies for identifying gene–gene interactions in hypertension. Ann Med 34:88–95
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):252–261
Naber CK, Husing J, Wolfhard U, Erbel R, Siffert W (2000) Interaction of the ACE D allele and the GNB3 825T allele in myocardial infarction. Hypertension 36:986–989
Ritchie MD, Hahn LW, Roodi N, Bailey LR, Dupont WD, Parl FF et al (2001) Multifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer. Am J Hum Genet 69(1):138–147
Ritchie MD, Hahn LW, Moore JH (2003) Power of multifactor dimensionality reduction for detecting gene–gene interactions in the presence of genotyping error, missing data, phenocopy, and genetic heterogeneity. Genet Epidemiol 24(2):150–157
Shen CD, Zhang WL, Sun K, Wang YB, Zhen YS, Hui RT (2007) Interaction of genetic risk factors confers higher risk for thrombotic stroke in male Chinese: a multicenter case–control study. Ann Hum Genet 71(Pt 5):620–629
Sudlow CL, Warlow CP (1997) Comparable studies of the incidence of stroke and its pathological types: results from an international collaboration. International Stroke Incidence Collaboration. Stroke 28(3):491–499
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):1617–1622
Tripodis N, Hart AA, Fijneman RJ, Demant P (2001) Complexity of lung cancer modifiers: mapping of thirty genes and twenty-five interactions in half of the mouse genome. J Natl Cancer Inst 93:1484–1491
Wang W, Prince CZ, Mou Y, Pollman MJ (2002) NOTCH3 signaling in vascular smooth muscle cells induces c-FLIP expression via ERK/MAPK activation. Resistance to Fas ligand-induced apoptosis. J Biol Chem 277(24):21723–21729
Wang Y, Zhang W, Zhang Y, Yang Y, Sun L, Hu S et al (2006) VKORC1 haplotypes are associated with arterial vascular diseases (stroke, coronary heart disease, and aortic dissection). Circulation 113(12):1615–1621
Wang T, Baron M, Trump D (2008) An overview of NOTCH3 function in vascular smooth muscle cells. Prog Biophys Mol Biol 96(1–3):499–509
World Health Organization (2003) The World Health Report 2003: shaping the future. World Health Organization, Geneva
Zhang WL, Yang XM, Shi J, Sun K, Hui RT (2006) Variant of SG13S114T/A in the ALOX5AP gene and the risk for stroke in a large Chinese cohort. Yi Chuan Xue Bao 33(8):678–684
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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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). https://doi.org/10.1007/s00439-009-0659-0
- Stroke Risk
- Multifactor Dimensionality Reduction
- MTHFR C677T
- Lacunar Infarction
- Plasma Homocysteine Concentration