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Multilocus genotypic association with vascular dementia by multifactor dimensionality reduction and entropy-based estimation

Objective We conducted a simultaneous analysis of candidate genetic loci for their genotypic association with the susceptibility to vascular dementia (VaD) to put forth the best model for predicting genetic susceptibility to VaD. Methods Individual-locus effects and their epistatic effects on susceptibility to VaD were simultaneously assessed by multifactor dimensionality reduction and entropy-based method. The 23 loci in 12 genes were studied in 207 VaD patients and age-matched and sex-matched 207 controls. Results The multifactor dimensionality reduction analysis revealed that the best single-locus candidate model included angiotensinogen (AGT) Thr235Met with testing accuracy (TA) of 58.31%, the best two-locus candidate model included AGT Thr235Met and transforming growth factor-&bgr;1 Pro10Leu with TA of 58.06%, the best three-locus candidate model was not significant (P>0.05), and the best four-locus candidate model included transforming growth factor-&bgr;1 Pro10Leu, AGT Thr235Met, sterol regulatory element binding protein 2 G34995T, and leukemia inhibitory factor T4524G with TA of 57.13% (P<0.05). The best four-locus model was, however, still in question because of the inconsistent best model selection by cross-validation. Synergistic epistatic effect of the best two-locus model was proven by entropy-based estimation. Conclusion The best predictor for genetic susceptibility to VaD was the single-locus model of AGT. The best two-locus model reflecting epistasis would be also employed for predicting its susceptibility. Further studies on the epistasis are to elucidate their underlying mechanisms.