Discussion
The current researches on candidate genes for MS are mainly focused on genes related to lipid metabolism disorders, hypertension and so on, when these genes related to different components of MS have polymorphisms or mutations, it may touch some risk factors or protective factors of MS, thereby affecting the development of MS. In the early years, researches on TBXAS1 gene mainly focused on inflammation, breast cancer and other diseases. In recent years, researches on this gene and diseases such as myocardial infarction, stroke, preeclampsia, has become a hot spot. Ulrich et al. 27 found that mutations in the TBXAS1 gene could alter protein function, which were related to inflammation and angiogenesis. Abraham et al.28 found that the NC_000007.14:g.139959792T>A mutation of the TBXAS1gene could moderately increase the risk of breast cancer. Lemaitre et al. 24 found NC_000007.14:g.139959792T>A was also related to ischemic stroke. Park et al. 29found that the +16184G> T polymorphism of TBXAS1 gene and TBXAS1-ht3 polymorphism frequency in cerebral infarction, especially in patients with small arterial occlusive cerebral infarction, increased significantly. In our study, there was polymorphism in the NC_000007.14:g.139985896C>T in the Han population in Shandong province of China. Comparison of the genotype and allele frequency distribution of the population suggested that there was no association between MS and the different genotypes of NC_000007.14:g.139985896C>T. However, MS is a syndrome of abdominal obesity, hyperglycemia, dyslipidemia and hypertension. This study observed and recorded the main clinical indicators related to the components of the MS. The results showed that in the MS population, there was no correlation between NC_000007.14:g.139985896C>T polymorphism and clinical indicators. This study further studied the genotype and allele frequencies and the different components of MS. The results showed that this gene polymorphism had no relationship with TG, blood pressure, FPG, abdominal obesity, and HDL-C, suggesting that NC_000007.14:g.139985896C>T polymorphism has no correlation with the incidence of MS. But although there was no difference in HDL-C levels among different genotype carriers, there were differences in HDL-C levels between the C and T alleles, suggesting that the C allele may have a regulatory effect on HDL-C. Therefore, is NC_000007.14:g.139985896C>T related to the prognosis of MS? To this end, we followed the population for 5 years to observe the relationship between the gene polymorphism and the prognosis of MS. This study found that NC_000007.14:g.139985896C>T polymorphism in the general population and MS population is associated with the incidence of ischemic stroke, which was similar to Lemaitre’s results that NC_000007.14:g.139985896C>T polymorphism is associated with ischemic stroke 24. Recent studies also found that,TBXAS1 gene polymorphisms had significant association with large-artery atherosclerosis stroke susceptibility and the level ofTBXAS1 expression 30. A study of Chinese people found that the TT genotype of TBXAS1 and T allele of NC_000007.14:g.139845571T>G increase susceptibility to ischemic stroke 31. However, the population of our study was more special, which were MS patients. At the same time, through screening of NC_000007.14:g.139985896C>T polymorphism and risk factors for ischemic stroke, it was found that the C allele was an independent protective factor for the incidence of ischemic stroke in the whole and MS population, individuals who carry the C allele have a reduced risk of stroke. Carriers of T allele are more likely to have ischemic stroke, but that was not an independent risk factor for ischemic stroke in this study, which may be influenced by other factors and need further study. Therefore, people carrying the C allele are less likely to suffer from ischemic stroke, which is more obvious when combined with MS. Patients with T allele should be better treated for MS to prevent the occurrence and development of ischemic stroke. The components of MS, such as hypertension, glucose and lipid metabolism, are genetically predisposed 10, 11. The heterogeneity of clinical phenotypes suggests that there may be genetic heterogeneity in MS, but no candidate genes have been reported could directly explain the onset and prognosis of MS. These genes mainly affect the occurrence and development of MS through the intermediate phenotype of MS development. Therefore, in this study, interaction analysis was performed of the NC_000007.14:g.139985896C>T polymorphism and the clinical characteristics of the subjects. Obesity is a risk factor of stroke 32, the results of this study showed that there were negative interactions between C allele and WC in the whole and MS population, suggesting that the C allele is a protective factor of ischemic stroke. With constant WC, the risk of ischemic stroke was reduced in carriers of the C allele. Hypertension is also a risk factor for stroke 32. In the present study, with the genotype of the whole and MS population unchanged, those with high SBP or DBP have a high risk of stroke, which is consistent with previous researches. Abnormal glucose and lipid metabolism are the main clinical feature of MS. In this study, the C allele had negative interactions with TG, HDL-C, and FPG. With the same TG, HDL-C, and FPG, the C allele carriers had a reduced risk of ischemic stroke. It is worth noting that the interaction of genes and clinical characteristics refers to combined effect, and cannot simply add the effects of various factors together. At the same time, a distinction should be made between biologically relevant and statistically relevant differences. Therefore, the statistical interactions found by association analysis need further study of its molecular mechanism to clarify its biological significance.
Some limitations in this study need to be considered. First, the hypothetical molecular mechanism how NC_000007.14:g.139985896C>T polymorphism affected the onset of ischemic stroke was not addressed in the present study. Second, further validation for the predictive value of this SNP as risk factor of MS components and pharmacogenetic indicator in independent cohorts.
Conclusions
This study has indicated that NC_000007.14:g.139985896C>T polymorphism was not associated with the pathogenesis or components of MS. However, it was related to the incidence of ischemic stroke in the whole and MS population, individuals who carry the C allele of NC_000007.14:g.139985896C>T have a reduced risk of stroke. These results suggest that this locus could be used as a therapeutic target for MS and providing a basis for genotype-guided individualized medication.
Disclosure statement
The authors have no conflicts of interest.