In the current study based on the Chinese Han population, we found that variants in MLL3(rs1137721) and TGFBR2(rs4522809) were associated with higher Type B AD risk. Inflammation reaction and lipid metabolism were associated with Type B AD, such as traditional risk factors smoking, Drinking, Hypertension, Diabetes, SBP, DBP. Meanwhile, HDL-C, LDL-C, WBC, were independent risk factors. Moreover, there exist MLL3-TGF-β pathway interactions among these Type B AD.
Based on lipid molecular analysis Study indicate the serum lipid composition that plays a key role in aortic aneurysm formation and AD occurrence [17]. Lipid metabolites HDL-C, LDL-C were independent risk factors for Type B AD patients [20]. Similar to Our study findings that TG, HDL-C, LDL-C associated with AD; multiple logistic regression analysis showed that LDL-C was no statistical significance, but the risk ratio is [OR=1.30(0.90-1.88), P=0.16]. The Histone 3 lysine 4 (H3K4) methyltransferases MLL3 regulates lipid metabolic processes including decreased white fat mass, and lipid accumulation in the brown adipose tissue and liver, improved glucose tolerance, increased energy expenditure, and bile acid (BA) levels. [16,17,18,21,]. MLL3/MLL4 as master enhancer epigenomic writers activated during adipogenesis [22]. MLL3(rs1137721 CT) genotype was the highest risk ratios, (OR=4.33, 95%CI=1.51-12.40). GMDR showed best the gene-gene interaction models (rs1137721 rs4522809) in affecting Type B AD risk. GMDR showed environment factors TG, TC with MLL3(rs1137721) worked together in affecting Type B AD risk. Clarified that MLL3 gene through by influencing the occurrence of lipid metabolic effects Type B AD development. However, long-term follow-up showed no statistical significance for all-cause mortality.
As identified by increased TGF-β signaling contributes to the complicated pathogenesis of aortic aneurysm [15]. TGFβ1 rs1800469 can affect the TGF-β1 plasma levels, located in the promoter region. Rs1800469 is also associated with heart diseases [23]. However, genetic associations between rs1800469 and Debakey III aortic dissection are still confounding. Two studies suggested that rs1800469 base mutation was associated with the presence of Abdominal Aortic Aneurysms in a UK cohort and Chinese cohort [24,25]. However, after adjusting for con-founders this association was lost. Our study logistic regression analysis showed rs1800469 dominant model [OR=3.43(1.04-11.30), P=0.04] was an independent risk factor for Type B AD patients.
The GMDR analysis certified that TGFBR2 rs4522809, smoking, dyslipidemia, and MLL3 rs1137721 are likely worked together in affecting Type B AD risk. Transforming growth factor-β (TGF-β) signaling pathway associated genes mutations can cause syndromic Thoracic Aortic Dissections (TAAD), such as Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), and Shprintzen-Goldberg Syndrome (SGS), and these syndromes potentially affect cardiovascular systems [3,4]. The cytokine transforming growth factor-b type II receptor (TGFBR2) was regulated by Fibrillin-1[26]. In Marfan patients, TGF-b levels are elevated, resulting from increased MMP activity and extracellular matrix breakdown [27]. Research in experimental aneurysms has repetitively revealed the activity of the TGF-β pathway in Thoracic Aortic Aneurysms [28]. the additional evidence of human mutations in genes encoding effectors of canonical TGF-β signaling has led to the hypothesis that aberrant TGF-B signaling drives aneurysm progression [29].
Aortic dissection (AD) has been recognized to be associated with an inflammatory process [30]. Chronic inflammation of the adventitia, media, and intima was increased in AD [31]. Our study also shows that WBC was associated with AD, logistic regress shows significant results. The GMDR analysis demonstrated that MLL3 rs1137721, drinking, WBC, hypertension, and diabetes mellitus probably worked together in affecting Type B AD risk. These findings showed that WBC, dyslipidemia, and the TGF-β pathway might influence Type B AD formation via the vascular fibrotic process, but the specific mechanism is unknown.
There were several limitations worth considering to this study. First, the sample size was small. It was found that the available sample sizes of 158 Type B AD cases and 197 controls had >60% and 85% statistical power to detect ORs of ~1.5 and ~1.8 for the association of the risk alleles with Type B AD. Therefore, the results should be requiring a sizable sample to verify. Second, the number of signaling pathway SNPs genotyped was limited. Seven polymorphisms were chosen and one gene-environment interaction affecting Type B AD risk was discovered. Several factors that influenced the presence of Type B AD, such as WBC, type 2 diabetes, hypertension, and atherosclerotic diseases, were found to have potential interactions with Type B AD risk; So, a more comprehensive study of complex correlation in Type B AD need to research.