Susceptibility of PCSK2 Polymorphism to Hirschsprung Disease in Southern Chinese Children.

Introduction: Hirschsprung's disease (HSCR) is a developmental defect of the enteric nervous system (ENS), which is caused by abnormal development of enteric neural crest cells. Its occurrence is caused by genetic factors and environmental factors. It has been reported that single nucleotide polymorphisms (SNPs) of proprotein convertase subtilisin/kexin type 2 (PCSK2) gene are associated with HSCR. However, the correlation of HSCR in southern Chinese population is still unclear. Methods: We assessed the association of rs16998727 with HSCR susceptibility in southern Chinese children using TaqMan SNP genotyping analysis of 2943 samples, including 1470 HSCR patients and 1473 controls. The association test between rs16998727 and phenotypes was performed using multivariable logistic regression analysis. Results: We got an unexpected result, PCSK2 SNP rs16998727 was not significantly different from HSCR and its HSCR subtypes: S-HSCR (OR = 1.08, 95% IC: 0.93~1.27, P_adj = 0.3208), L-HSCR (OR = 1.07, 95% IC: 0.84~1.36, P_adj = 0.5958) and TCA (OR = 0.94, 95% IC: 0.61~1.47, P_adj = 0.8001). Conclusion: In summary, we report that rs16998727 (PCSK2 and OTOR) is not associated with the risk of HSCR in southern Chinese population.

A LncRNA gene polymorphism (rs1814343) is associated with the risk of coronary artery lesions in southern Chinese Kawasaki disease patients.

BACKGROUND: Kawasaki disease (KD) is a multisystemic angiitis, and its most disastrous complication is coronary artery lesions (CALs). Recently, the role of long non-coding RNAs (lncRNAs) in KD has been reported. rs1814343 is a lncRNA, but the relationship between the lncRNA rs1814343 polymorphism and KD risk remains elusive. METHODS: We enrolled 1625 Kawasaki disease patients (583 patients with CAL and 1042 without CAL) and 1000 healthy controls from a southern Chinese population. We genotyped the rs1814343 C > T polymorphism in KD and control patients using the TaqMan method. The odds ratio (OR) and 95% confidence interval (CI) were used to estimate the strength of the association. RESULTS: There was no significant association between the lncRNA rs1814343 C > T polymorphism and KD susceptibility. However, we stratified patients in this study by CAL and sex. First, compared with the control groups, we found that the rs1814343 genotype increased risk for KD patients with CAL (TT vs. CC + CT: OR = 1.36, 95% CI = 1.08-1.71, p = 0.009). Moreover, when KD patients were stratified by CAL, the TT genotypes of this lncRNA polymorphism contributed to a relatively higher occurrence of KD with CAL than that was found in the CC/CT genotype patients (TT vs. CC + CT: OR = 1.35, 95% CI = 1.07-1.69, p = 0.011). In addition, our research suggested that the TT variant genotype in the lncRNA rs1814343 had an obvious risk of KD with CAL susceptibility in male children. CONCLUSION: The lncRNA rs1814343 C > T polymorphism was related to higher susceptibility of KD with CAL.

Plasma single-stranded DNA autoantibodies in the diagnosis of Hirschsprung's disease.

Background: Hirschsprung's disease (HSCR) is a neonatal enteric nervous system (ENS) disease characterized by congenital enteric ganglion cell loss. The only treatment is aganglionic bowel segment resection and innervated bowel segment reconstruction. Delayed diagnosis and treatment cause postoperative complications such as intractable constipation and enterocolitis. Existing preoperative HSCR diagnostic methods have shortcomings such as false positives, radiation and invasiveness. Methods: We used the robust linear model (RLM) for normalization and the M statistic for screening plasma human autoimmune antigen microarrays and quantitatively assessed single-stranded DNA (ssDNA) antibody levels with enzyme-linked immunosorbent assay (ELISA). Results: The autoimmune antigen microarray revealed that autoantibodies were higher in HSCR plasma than in disease control (DC) and healthy control (HC) plasma. ssDNA antibodies in HSCR plasma were significantly higher than those in DC and HC plasma. Quantitative ssDNA antibody level detection in plasma by ELISA showed that HSCR (n = 32) was 1.3- and 1.7-fold higher than DC (n = 14) and HC (n = 25), respectively. ssDNA antibodies distinguished HSCR from non-HSCR (HC and DC), achieving an area under the curve (AUC) of 0.917 (95% CI, 0.8550-0.9784), with a sensitivity of 96.99% and a specificity of 74.63%. Conclusion: ssDNA antibodies in plasma can serve as a diagnostic biomarker for HSCR in the clinic.

Susceptibility of ECE1 polymorphisms to Hirschsprung's disease in southern Chinese children.

Background: Hirschsprung's disease (HSCR) is currently considered to be a congenital gastrointestinal malformation caused mainly by genetic factors. Endothelin Converting Enzyme-1 (ECE1) has been reported to be associated with HSCR. However, the relationship between ECE1 single nucleotide polymorphism (SNP) rs169884 and HSCR in the southern Chinese population remains unknown. Methods: 1,470 HSCR patients and 1,473 controls from a southern Chinese population were recruited. The intronic SNP rs169884 in ECE1 was genotyped in all samples. We tested the association between rs169884 and HSCR under various genetic models. We also evaluated the effect of rs169884 on HSCR subtypes, including short-segment HSCR (S-HSCR), long-segment HSCR (L-HSCR) and total colonic aganglionosis (TCA). External epigenetic data were integrated to investigate the potential biological function of rs169884. Results: Chromatin states data from derived neuron cells or fetal colon tissue revealed that rs169884 might control ECE1 expression through regulating its enhancer function. We did not find a significant association between rs169884 and HSCR. For HSCR subtypes, although no significant associations were detected between rs169884 and S-HSCR (OR = 1.00, 95% CI: 0.89∼1.12, Padj = 0.77) or TCA (OR = 1.00, 95% CI: 0.72∼1.38, Padj = 0.94), we found that rs169884 could increase the risk of L-HSCR (OR = 1.23, 95% CI 1.02∼1.45, Padj = 0.024). Conclusion: These results suggested that rs169884 might play a regulatory role for ECE1 expression and increase susceptibility of L-HSCR in southern Chinese children.