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.