Discussion
In the present study, we enrolled a cohort of 474 cases with sepsis and 678 controls to evaluate the association betweenLincRNA-NR_024015 rs8506 polymorphism and the sepsis susceptibility among southern Chinese children. The result showed that the carriers of rs8506 TT genotype had a significantly increased risk of sepsis when compared with that carrying CC/CT genotypes. Interestingly, the stratified analysis revealed that the increased risk level of rs8506 TT variant appeared more obvious in the children of 12–60 months old and female. Moreover, we also found that the rs8506 TT variant showed significantly elevated risk of sepsis in the subgroup of the patients who were in the early stage of sepsis or alive. Therefore, our findings provided evidences that LincRNA-NR_024015 rs8506 TT genotype might be associated with the susceptibility of sepsis in a southern Chinese child population.
Long non-coding RNAs (lncRNAs) are a type of non-protein-coding RNAs which exceed 200 nucleotides in length[10, 13]. It has been suggested that lncRNAs play important roles in the pathogenesis of various diseases through chromatin rearrangement, transcriptional control as well as post-transcriptional processing[10, 13]. However, little is known about the relationship between lncRNAs and the sepsis susceptibility[11, 31]. In the present study, we found thatLincRNA-NR_024015 rs8506 TT genotype was notably associated with an increased risk of sepsis. To our knowledge, this is the first study to evaluate the relationship of the rs8506 polymorphism with sepsis risk in a southern Chinese child population.
LincRNA-NR_024015 (gene ID: 732253) is also known as testis developmental related gene 1 (TDRG1 ). TDRG1 was initially identified as a novel human testis-specific gene which served as a regulator in sperm motility and the development of testicular germ cell tumors[32, 33]. Recent studies have suggested that lncRNATDRG1 might play important roles in tumor progression in several cancer types including cervical[14], esophageal[26], ovarian[17] and endometrial carcinoma[16]. Chen et alprovided evidences that lncRNA TDRG1 might directly bound to VEGF-A protein and upregulated its expression, thus promoting the progression of endometrial carcinoma[16]. Moreover, lncRNA TDRG1 and VEGF were found to be co-expressed and remarkably upregulated in fibrovascular membranes from diabetic retinopathy patients than those from epiretinal membrane[34]. These reported data indicated that lncRNA TDRG1 might be beneficial to stimulate the VEGF pathway[34]. VEGF is a potent mediator that not only increases the vascular permeability, but also promotes leukocytes adhesion by eliciting the expression of adhesive molecules[18-20]. Actually, emerging data have suggested that circulating VEGF levels were elevated during the development of sepsis[21-25] and the levels of this factor were associated with sepsis severity and mortality[21-23]. Blockade of VEGF signaling in a mouse model might have beneficial effects on the survival of sepsis by decreasing inflammatory responses and endothelial permeability[35]. Importantly, the expression level of lncRNA TDRG1 in esophageal tumor tissues with rs8506 CT and TT genotype was significantly higher than those with rs8506 CC genotype[26]. Therefore, in combination with the findings in our study, we speculated that rs8506 TT genotype might increase the risk of sepsis via upregulating the levels of lncRNATDRG1 and VEGF. Further study is needed to confirmed this possibility in the future.
Epidemiological studies have showed that global sepsis apparently occurred in females and young children below 5 years old[2]. Similar to the present study, the increased risk of the rs8506 TT variant genotype was more evident in the children of 12–60 months old and in females, as compared with the CC/CT genotypes. Furthermore, it is surprising in our study, the rs8506 TT genotype was markedly associated with an increased sepsis risk among sepsis and survivor subgroup of the patient cohort, but not severe sepsis, septic shock or non-survivor. Owing to the robustly low frequency of rs8506 TT genotype in the enrolled cohort, we considered that the sample size was not enough to test the power of analysis. The current study is only an investigation that focus on the relationship between gene polymorphism and disease susceptibility. Therefore, more mechanistic studies are needed to confirm the roles of lncRNA TDRG1 rs8506 TT in the progression of sepsis in children.
Although this is the first study to evaluate the association between lncRNA TDRG1 rs8506 polymorphism and sepsis risk in southern Chinese children, several possible limitations should be addressed in present study. First, there are only 474 sepsis patients and 678 controls included. Therefore, the sample size in the current study might have impact on the test power of statistical analysis. Second, only rs8506 T allele was under investigation in the present study, other lncRNA TDRG1 gene polymorphisms with potential function remain to be took into consideration. Third, it has been shown that many factors (i.e., living environment, social-economic factor, population education) have impact on the incidence of sepsis[2, 36]; however, we could only collect frequency-matched cases and controls by age and gender due to lack of these information.
In summary, we verified a significant association between lncRNATDRG1 rs8506 TT genotype and increased sepsis susceptibility in southern Chinese children, especially for children aged 12–60 months, females, and those with early stage of sepsis. Future studies with larger sample size and mechanistic experiments should be conducted to strengthen our findings.