Abstract
Background
RET and Semaphorin 3 (SEMA3) common variants have been associated with Hirschsprung disease (HSCR), but their genetic interactions for development of HSCR is not established yet. To determine the joint effects of RET gene, rs2435357, and SEMA3 gene with three markers; rs1583147, rs12707682, and rs11766001 polymorphisms in Indonesian HSCR patients.
Methods
Sixty HSCR patients and 115 non-HSCR controls were included in this study. Four genetic markers of the RET and SEMA3 were examined in 175 DNAs using TaqMan Genotyping assay. Case-control analysis and transmission disequilibrium test (TDT) were used to determine an association between four genetic markers and HSCR. We used a P value of <0.013 for a significant association.
Results
There was a strong association between RET rs2435357 marker and HSCR either by case-control analysis (OR =4.46, P=2.5×10−8) or TDT (P=4.2×10−6), but not SEMA3 rs1583147 (OR =1.9, P=0.023 and P=0.11, respectively) and rs12707682 (OR =1.5, P=0.06 and P=0.041, respectively). Two locus analyses of variants revealed that RET rs2435357 (TT), in combination with SEMA3 rs1583147 (CT) or rs12707682 (CC), were associated with the augmented disease risks of HSCR (OR =2.88, P=0.016 and OR =19.9, P=0.005, respectively) compared with a single variant of SEMA3 rs1583147 or rs12707682. Moreover, the SEMA3 rs11766001 frequencies in HSCR patients and non-HSCR subjects were 1.7% and 0.8% (P=0.48), respectively.
Conclusions
The genetic effects of SEMA3 genotypes are epistatic to RET. The rarity of SEMA3 rs11766001 in Indonesia could be explained by the founder effect.
Keywords: Hirschsprung disease, RET, Semaphorin 3, polymorphisms, rare variant