Association Analysis of SLC6A20 Polymorphisms With Hirschsprung Disease
Jin Sol Lee1, Jung-Tak Oh, Jeong-Hyun Kim
1†Department of Pediatric Surgery, Severance Children's Hospital, Yonsei University College of Medicine ‡Division of Pediatric Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine §Department of Pediatric Surgery, Asan Medical Center, University of Ulsan College of Medicine ||Department of Pediatric Surgery, Seoul National University Children's Hospital ¶Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Gyeonggi #Department of Genetic Epidemiology, SNP Genetics, Inc **Department of Physiology, College of Medicine, Hanyang University ††Research Institute for Basic Science, Sogang University, Seoul, Republic of Korea.
Purpose:
Hirschsprung disease (HSCR) is a congenital and heterogeneous disorder, which is caused by no neuronal ganglion cells in part or all of distal gastrointestinal tract. Recently, our genome-wide association study has identified solute carrier family 6, proline IMINO transporter, member 20 (SLC6A20) as one of the potential risk factors for HSCR development. This study performed a replication study for the association of SLC6A20 polymorphisms with HSCR and an extended analysis to investigate further associations for subgroups and haplotypes.
Methods:
For the replication study, a total of 40 single nucleotide polymorphisms (SNPs) of SLC6A20 were genotyped in 187 HSCR subjects composed of 121 short-segment HSCR, 45 long-segment HSCR (L-HSCR), 21 total colonic aganglionosis, and 283 unaffected controls. Imputation was performed using genotype data from our genome-wide association study and this replication study.
Results:
Imputed meta-analysis revealed that 13 SLC6A20 SNPs (minimum P = 0.0002 at rs6770261) were significantly associated with HSCR even after correction for multiple comparisons using false discovery rate (FDR) (minimum PFDR = .005). In further subgroup analysis, SLC6A20 polymorphisms appeared to have increased associations with L-HSCR. Moreover, haplotype analysis also showed significant associations between 2 haplotypes (BL3_ht2 and BL4_ht2) and HSCR susceptibility (PFDR < .05).
Conclusions:
Although further replications and functional evaluations are required, our results suggest that SLC6A20 may have roles in HSCR development and in the extent of aganglionic segment during enteric nervous system development.
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