Potential association of VAMP5 polymorphisms with total colonic aganglionosis in Hirschsprung disease

Background: Hirschsprung disease (HSCR) is a congenital bowel disease caused by the absence of nerve cells in portions of the intestine. Our recent genome-wide association study has identified a variant (rs1254900) of vesicle-associated membrane protein 5 (VAMP5) as a potential risk locus for total colonic aganglionosis (TCA) in HSCR. In addition, VAMP5 is a member of the VAMP/synaptobrevin protein complex, which participates in nerve signal transduction by regulating the vesicular fusion of the neurotransmitter in synaptic transmission. Methods: A total of 11 single nucleotide polymorphisms (SNPs), including those in the functionally important coding region, were selected on the basis of linkage disequilibrium and genotyped in 187 HSCR patients and 283 unaffected controls by using a TaqMan assay. Logistic analysis was conducted to investigate the possible association between VAMP5 SNPs and the risk of HSCR. Key Results: Genetic variants of VAMP5 showed increased association signals in the TCA subgroup of HSCR patients (minimum p = 9.69 × 10⁻⁵, OR = 3.93 at rs10206961) compared to other subgroups, even after Bonferroni correction (p_corr = 0.002). In haplotype analysis, three haplotypes (BL1_ht1, BL2_ht1, and BL2_ht2) were associated with the risk of TCA (minimum p_corr = 0.005). In additional combined analysis after imputation based on our previous GWAS, five SNPs still retained significant associations with the TCA subtype (minimum p_corr = 0.006 at rs10206961). Conclusions & Inferences: Considering that differential genetic effects on the development of the enteric nervous system, our results suggest that VAMP5 may be associated with the TCA of HSCR. However, further replications and functional evaluations are required.