The Correlation Between Single Nucleotide Polymorphism In FBN-1 Gene (rs2118181) And Sporadic Acute Aortic Syndrome In Chinese Han Population

Part I The correlation between single nucleotide polymorphism in FBN-1 gene (rs2118181) and sporadic acute aortic syndrome in Chinese Han population.Acute aortic syndrome (AAS), one of the most emergent diseases, refers to a group of emergent conditions that involve aorta. The cause of AAS is multifactorial. Besides the environmental and physiological factors, gene mutation is an important factor. It was proved that some inherited connective tissue diseases were associated with AAS, such as Marfan syndrome, Ehler-Danlos syndrome, and so on. Several studies have revealed that there is a relation between the single nucleotide polymorphism and sporadic AAS. Lemaire et al. reported that FBN-1 rs2118181 was associated with sporadic thoracic aortic dissection (TAD) in Caucasian. However, a small size research (n=51) by Wang Y et al. showed that there was no significant correlation between FBN-1 rs2118181 and thoracic aortic disease (Thoracic aortic disease and Thoracic aortic aneurysm). Nevertheless, the conclusion was not pervasive for the poor samples. What's more, intramural haematoma (IMH) and penetrating aortic ulcer (PAU) were not enrolled.ObjectiveOur study was designed to investigate the correlation between single nucleotide polymorphism in FBN-1 gene (rs2118181) and sporadic acute aortic syndrome in Chinese Han population.MethodsThis study was designed as a Case-Control research. Case and control patients were individually matched with regard to their gender, age (difference<5 years), body mass index (BMI, difference<3). Two groups were also matched by frequency of hypertension and diabetes mellitus (group matching).Patients of Chinese Han, who were diagnosed as AAS (AD/IMH/PAU) in Guangzhou General Hospital of Guangzhou Military Command, Guangdong Provincial People's Hospital, Jiangmen Central Hospital or Sun Yat-sen Memorial Hospital Sun Yat-sen University between August 25th 2014 and February 1st 2016, were enrolled. The diagnosis of AAS was based on the clinical characteristics and imaging techniques, including echocardiography and computed tomography angiography. Patients with syphilis, aortitis, bicuspid aortic valve, Marfan syndrome, familial thoracic aortic aneurysms and dissection, Ehlers-Danlos Syndrome, Loseys-Dietz syndrome, Turner syndrome or traumatic aortic disease were excluded from the study. Controls were recruited in the Out-patients Departments and Health Examination Center, who were found to have no aortic diseases by echocardiography, chest X-ray and physical examination. Written informed consent was obtained from all subjects participating in this study.To compare the different types of AAS, AAS cases were divided into some subgroups. They were divdided into Stanford type A Subgroup and type B Subgroup by Stanford classification.They were also divided into AD Subgroup, IMH Subgroup and PAU Subgroup by the morphology of aorta CTA.For calculation the required number of participants, the software PASS 11.0.7 were used. On The basis of Minor Allele Frequency (MAF) for rs2118181 in Chinese Han population (www.hapmap.ncbi.nlm.nih.gov), the study had more than 80% statistical power to detect an association (at P<0.05) with an OR of 1.8. It turned out the number of case and control groups were both 203.All data were analyzed using the statistical software SPSS 21.0 for Windows. Distributions of continuous variables were expressed as mean ± SD, or median and interquartile ranges M (P25-P75). Statistical significance for differences in quantitative variables was tested by the Student's independent-samples t test or Wilcoxon rank sum test. Categorical data are presented as frequencies (%). Differences between categorical variables, genotype, allele frequencies, and Hardy-Weinberg equilibrium were tested by X2 analysis or Fisher's exact test. A multiple logistic regression analysis was used to adjust the age, gender, BMI, hypertension, smoking and diabetes mellitus. Odds ratio (OR) and 95% confidence interval (CI) were calculated. All tests were 2-tailed, and a P<0.05 was set for statistical significant.Results1.206 patients with AAS (174 male,32 female) and 206 controls (172 male,34 female) were enrolled. Among the AAS group there were 148 AD,54 IMH and 4 PAU. There was no significant difference in age, BMI, gender, hypertension and diabetes mellitus history between cases and controls. However,the hypertension awareness and treatment rate of AAS group were significantly lower than the controls'(P<0.05). And, the proportion of Level 3 hypertension, smoking, fasting glycaemia (FG) and serum creatinine (SCr) were significantly higher than controls(P<0.05).2. The rs2118181 genotype frequencies were 4.9% for CC,33% for CT, and 62.1% for TT in cases; while they were 6.8% for CC,41.3% for CT, and 51.9% for TT in controls. There was no significant difference among the different genotypes (P>0.05). The minor allele frequency of rs2118181 in AAS was significant lower than in controls (21.3% vs. 27.4%, P=0.043). In the analysis of dominant genetic model [(CC+CT)/TT] between two groups, it was found out that carriers of C allele had a less risk of AAS with an adjusted OR 0.66(95%CI:0.44-0.99, P=0.044). However, there was no significant difference in the recessive genetic model [CC/(TT+CT)].3. In the contrast between the subgroups and control, we only found significant difference between IMH subgroup and controls:the MAF of rs2118181 in IMH subgroup was significant lower than in AAS (16.7% vs.27.4%, P=0.022), and carriers of rs2118181 C allele were at less risk for IMH, compared with non-carriers:the adjusted OR was 0.47(95%CI:0.24-0.90, P=0.024).4. There was no significant difference on the frequencies of rs2118181 genotype between the subgroups:IMH and AD subgroup, Stanford type A and type B subgroup (P>0.05).ConclusionsThe rs2118181 polymorphism of FBN-1 gene is correlated to the sporadic AAS, especially to IMH in Chinese Han population. Furthermore, the carriers of TT genetype are vulnerable to AAS, especially to sporadic IMH, compared to the non-carriers.Part II The correlation between single nucleotide polymorphism in FBN-1 rs2118181gene and the early progress of sporadic IMH in Chinese Han populationObjectiveOn the base of findings in Part I, we further investigated the influence of gene polymorphism on the progress of sporadic IMH in Chinese Han population.MethodsThis study was preceded between August 25th 2014 and January 31st 2016 in Guangzhou General Hospital of Guangzhou Military Command, Guangdong Provincial People's and Sun Yat-sen Memorial Hospital Sun Yat-sen University. Patients of Chinese Han, who were diagnosed as IMH without severe complications and had a complete document of aorta computed tomography angiography (CTA), were enrolled. Our therapeutic strategies for all patients were medical therapy with frequent follow-up imaging studies and timed surgical repair in case with progression.Patients, who needed an emergency surgery or thoracic endovascular aortic repair because the progression of disease, or with syphilis, aortitis, bicuspid aortic valve, Marfan syndrome, familial thoracic aortic aneurysms and dissection, Ehlers-Danlos Syndrome, Loseys-Dietz syndrome, Turner syndrome or traumatic aortic disease were excluded from the study.The criteria of early progress of IMH was as follows: ? recurrent aortic pain regardless of the optimal medical therapy. ? the present of the following signs in reviewed aorta CTA:enlargement of aortic diameter (? lmm, compared than the first CTA results), hematoma and ulcer diameter, new appearance of aortic ulcer, appearance of overt aortic dissection and appearance of contrast agent in hematoma. The patients were divided into two groups depending on the clinical symptoms and reviewed CTA results:invasive cases (group A, n=23) and non-invasive cases (group B n=13).Laboratory testing results including white blood cell counts (WBCc), neutrophil granulocyte proportion (N%), blood platelet count (PLTc), SCr, FG and low density lipoprotein cholesterol (LDL-C) were collected. The aorta was divided into 7 segments for a detailed evaluation of the longitudinal extent of IMH and the location of any PAU. These 7 segments were the ascending aorta, aorta arch, and proximal descending, mid-descending, distal descending, suprarenal abdominal, and infrarenal aorta. Imaging studies including the presence of pleural effusion and aortic ulcer, the largest diameter of hematoma, the segments involved by hematoma were collected. The genotypes of rs2118181 gene were also determined.All data were analyzed using the statistical software SPSS 21.0 for Windows. Distributions of continuous variables were expressed as mean ± SD, or median and interquartile ranges M (P25-P75). Statistical significance for differences in quantitative variables was tested by the Student's independent-samples t test or Wilcoxon rank sum test. Categorical data are presented as frequencies (%). Differences between categorical variables, genotype, allele frequencies, and Hardy-Weinberg equilibrium were tested by X2 analysis or Fisher's exact test. Factors that had statistic difference with P value<0.05 in univariate analysis, were taken in to the multiple analysis. A multiple logistic regression analysis was used to evaluate the independent effects on the progress of IMH. A receiver-operating characteristics (ROC) curve analysis was performed to determine the best cutoff value for predicting the early progress of IMH. Odds ratio (OR) and 95% confidence interval (CI) were calculated. All tests were 2-tailed, and a P<0.05 was set for statistical significant.Results1.36 patients (male 28, female 8) of IMH were enrolled. After optimal medical therapy,13patients (36.1%) showed a regression of hematoma,23 patients reached the criteria of progress of IMH in our study:lpatient (2.8%) having overt AD; 2 patients (5.6%) with recurred aortic pain; 8 patients (22.2%) with a progression of hematoma,3 patients (8.3%) with an appearance of contrast agent in hematoma and 9 patients (25%) with new appearance or enlargement of ulcer presented.2. There were no significant differences on PLT count, FG, LDL-C, SCr (P>0.05). However, the WBCc was significant higher in group A than group B (13.9±4.0 vs.11.0±1.9 ×109/L, P=0.006).3. The aortic segments having IMH in group A were more than those in group B (5.1 ± 1.0 vs.4.2± 1.2, P=0.020). And the proportion of IMH with ulcer in group A was significant higher than that in group B (65.2% vs.23.1%, P=0.015).4. The frequency of rs2118181 TT genotype in group A was significant higher than that in group B (82.6% vs.38.5%, P=0.020).5. Factors including WBCc, aortic ulcer, segments having IMH and dominant genetic model were taken into the multiple logistic regression analysis. WBCc and aortic ulcer were found to be the independent risk on the early progress of IMH, with an OR 1.6 (95%CI:1.04-2.48, P=0.035) and 27.1 (95%CI:1.80-408.42, P=0.017) respectively.6. The area under the curve on ROC curve of WBCc was 0.73 (95%CI:0.57-0.89, P=0.022). The cutoff of WBCc to predicting the early progress of IMH was 12.24 X 109/L, with an sensitivity of 65.2%, and specificity of 76.9%.ConclusionsThere was a correlation between the aortic ulcer, WBCc (>12.24 × 109/L) in admission and the early progress of sporadic IMH in Chinese Han population. However, the relationship between the single nucleotide polymorphism in rs2118181 gene and the early progress of sporadic IMH in Chinese Han population was not confirmed in this study.