HSCR results from many genetic factors. Various studies have shown that candidate gene, including SOX10 and Glial cell line-Derived Neurotrophic Factor (GDNF), are important for the diagnosis of HSCR. Several researches have shown the etiology of HSCR. However, the precise mechanism remains unknown. This study showed that two SNPs (rs8104023, rs4252546) in the IL-11 gene were unrelated to the risk of HSCR in Chinese populations. Furthermore, IL-11 gene polymorphisms may play a role in HSCR-associated enterocolitis.
IL-11 belongs to the IL-6 cytokine family and can stimulate megakaryocytopoiesis, which is essential in pro-inflammatory functionality . IL-11 has been reported to affect the progress of the enteric nervous system . The fluctuation in IL11 protein levels influences neural maturation and inflammation that is often seen as a characteristic symptom of HSCR. In the study of Kim et al., nine SNPs of the IL11 gene were selected, and several SNPs were identified to have a statistical and significant association with HSCR. The frequencies of rs4252546 and rs8104023 were higher in HSCR cases than those in unaffected subjects . In contrast, the study by Haase et al. showed that these two SNPs in the IL11 gene were not significantly related to HSCR of the German population (128 healthy controls and 103 HSCR patients). This study further explored whether the same situation would be observed in a larger Chinese population. In this study, SNP rs4252546 is a putative binding site of NF-1 and may affect gene expression (pcorr = 9.70 9 10_4 in combined analysis) . Besides, rs4252546 and rs8104023 exist in a potential regulatory region and an intronic region, respectively. These findings reveal that the IL-11 gene may interact with other genes to exert a limited role in regulating and controlling the aganglionic segment during the ENS development.
However, no study has explored the relationship between IL-11 gene polymorphisms and susceptibility to HSCR in a Southern Chinese population. This study found no association between the 2 SNPs with HSCR. However, small sample size may negatively affect ethnic diversity or sample size, possibly reflected by different genetic backgrounds. The independence test (Fig. 1) shows that rs1126760 exhibited limited LD with all other SNPs in the CEU. Rs8104023 and rs4252546 exhibited moderate to high LD between each other in the CHB.
Our results showed no significant association with HSCR regarding enterocolitis. Similarly, research by Liao et al. provided evidence that IL-11 rs8104023 is not significantly associated with the risk of gastric cancer based on 880 Chinese cases . A study by Haase et al. showed that IL-11 rs4252546 has no significant associations with HSCR based on a German population (103 cases and 128 controls) . This might be due to limited samples. Therefore, the patients were categorized into different groups based on clinical HSCR subtypes. This methodology showed an increased association of rs8104023 with S-HSCR and L-HSCR both before and after surgery. HEAC is a well-known complication of HSCR that occurs at any stage and may potentially cause death. There are numerous theories explaining the occurrence of HEAC, but the reasons remain unclear. According to the study by Greenwood-Van Meerveld et al., IL-11 restores the ability of longitudinal muscles, thus reversing the inflammatory response and producing active tension in both the jejunum and colon . This demonstrates that the occurrence of HSCR-associated enterocolitis may be reduced by IL-11 polymorphisms. IL-11 promoter variants may modulate the expression of IL-11 to increase the susceptibility to HEAC, thereby leading to abnormal neuronal maturation and colonic inflammation. However, the functional mechanism of IL-11 and HEAC is unclear, thereby requiring further studies with larger sample sizes, different populations, and functional evaluations to verify these results.