1 Characteristics of participants
The General characteristics of study participants were shown in Table 1. A total of 173 patients with DeBakey type III AD and 335 normal subjects were enrolled in the study. There were 144 males and 29 females in case group, with an average age of 51.54 ± 11.53 years. In control group, there were 193 males and 142 females, with an average age of 57.12 ± 11.39 years. There were significant differences between the case and control groups: systolic blood pressure (SBP, P < 0.001),diastolic blood pressure (DBP, P < 0.001), body mass index (BMI, P < 0.001), white blood cell (WBC, P < 0.001), blood urea nitrogen (P = 0.053), creatinine (P = 0.003), uric acid (P = 0.005), glucose (P < 0.001), glycosylated serum protein (GSP, P < 0.001), high density lipoprotein cholesterol (P < 0.001), hypertension (P < 0.001), diabetes (P = 0.035), smoking (P < 0.001) and drinking (P < 0.001). There were not significantly different between case and control groups including triglyceride (P = 0.854), total cholesterol (P = 0.935), low density lipoprotein cholesterol (P = 0.692).
2 The genotype and allele frequencies
The genotype and allele distribution characteristics of SNPs in case and control group were shown in Table 2. The genotype distributions of 4 SNPs for both case and control participants were in accordance with the Hardy-Weinberg equilibrium. The genotype frequencies of MYH11 rs115364997 (P = 0.044), TGFBR1 rs1626340 (P = 0.030) and the allele frequencies of MYH11 rs115364997 (P = 0.011) were difference between case and control group. The genotype frequencies of MYH11 rs117593370, TGFB1 rs1800469, allele frequencies of MYH11 rs117593370, TGFB1 rs1800469 and TGFBR1 rs1626340 did not differ between the case and control groups (P > 0.05).
3 Analysis of the association between genetic models and aortic dissection risk
We further assessed the association between genetic models and the risk of Debakey type Ⅲ AD. MYH11 rs115364997 dominant model AG+GG genotype (OR = 1.629; 95%CI: 1.077-2.462, P = 0.020) and TGFBR1 rs1626340 dominant model GA+AA genotype (OR = 1.500; 95CI: 1.032-2.181, P = 0.033) were found to be the risk factors for AD. But there was no difference on genotypes of MYH11rs117593370, TGFB1rs1800469 (P > 0.05) (Table 3).
4 Gene-gene interaction
GMDR was used to analyze the interaction of the four SNPs (Table 4). The best model is the two-factor interaction model of MYH11 rs115364997 and TGFBR1 rs1626340 with the maximum CVC (10/10) after 1000 permutation tests, and the maximum values of sign test (10) and testing balance accuracy (0.5600), P = 0.0010.
5 Gene-environment interaction
GMDR was used to analyze the association between gene-environment interaction and AD risk (Table 5). Possible risk factors including the four SNPs, smoking, drinking, hypertension, type 2 diabetes, BMI ≥ 24kg/m2 and dyslipidemia were considered in the model. The best model is the seven-factor interaction model of MYH11rs115364997, TGFB1rs1800469, TGFBR1rs1626340, smoking, drinking, hypertension, BMI ≥ 24kg/m2 with the maximum CVC (10/10) after 1000 permutation tests, and the maximum values of sign test (10) and testing balance accuracy (0.7673), P = 0.0010. The potential interaction of drinking and BMI ≥ 24kg/m2 on type III AD risk was discovered (CVC = 10/10; P = 0.0010). In addition, we found that the two-factor, six-factor, and eight-factor models are also statistically significant (P = 0.0010) and maximum cross-validation consistency (10/10). However, compared with the seven-factor model, these models have lower values of test balance accuracy.
5 Associations of 4 SNPs with clinical outcomes in Debakey type Ⅲ aortic dissection patients
At the end of the study, a total of 28 patients died of recurrence of aortic dissection, and 94 patients had recurrent chest pain. The association of Tag SNPs and clinical outcomes in Debakey type Ⅲ aortic dissection patients were assessed by Kaplan-Meier method, the log-rank test (Figure 1). Patients with these genotypes are associated with a higher mortality risk: dominant models of MYH11 rs115364997 AG+GG genotype (HR = 2.443; 95%CI:1.096-5.445, P = 0.029), TGFB1 rs1800469 AG+GG (HR = 2.303; 95%CI:1.069-4.96, P = 0.033), and additive models of MYH11 rs115364997 (AG vs. AA) (HR = 2.754; 95%CI: 1.187-6.391, P = 0.018), TGFB1 rs1800469 (AG vs. AA) (HR = 2.893; 95%CI: 1.241-6.448, P = 0.013). No statistically differences were found between mortality risk and genetic models of MYH11 rs117593370, TGFBR1 rs1626340 (P > 0.05) (Table 6).
The same statistical methods were used in risk of recurrent chest pain. As a result, TGFB1 rs1800469 dominant model AG+GG genotype was found to be associated with a higher risk of recurrence of chest pain (HR = 1.566; 95%CI: 1.018-2.378, P = 0.041). No statistically differences were found between mortality risk and other genetic models (P > 0.05) (Table 7).