Genetic variants in RET and risk of Hirschsprung's disease in Southeastern Chinese: a haplotype-based analysis

Jinfa Tou,Hong Yang,Rong Zhong,Qixing Xiong,Shengyu Duan,Weiguang Liu,Li Liu,Li Wang,Qinglong Gu,Hui Li,Ying Wang

doi:10.1186/1471-2350-12-32

Abstract

BackgroundHirschsprung's disease (HSCR) is a classic oligogenic disorder. Except inactivating mutations of RET, some single nucleotide polymorphisms (SNPs) are identified to be associated with the risk of HSCR. This study was conducted to examine the impact of the haplotypes profile of the reported associated SNPs of RET on the risk of HSCR in a Southeastern Chinese population.MethodsGenotypes of -5G > A (rs10900296), -1A > C (rs10900297), c135G > A (rs1800858), c1296A > G (rs1800860), and c2307T > G (rs1800861) were analyzed in 123 HSCR patients and 168 controls by polymerase chain reaction amplification and direct sequencing. Associations with risk of HSCR were estimated by odds ratio (OR) and their 95% confidence intervals (95% CI) using logistic regression.ResultsWe observed a significantly increased risk of HSCR associated with the RET -5AA (OR = 17.75, 95% CI = 7.34-42.92), -1CC (OR = 10.89, 95% CI = 3.13-37.85), 135AA (OR = 13.61, 95% CI = 6.14-30.14), 1296GG (OR = 2.40, 95% CI = 1.38-4.18) or 2307GG (OR = 9.79, 95% CI = 4.28-22.43) respectively. The five SNPs were in strong linkage disequilibrium. The haplotype A-C-A-G-G (OR = 5.06, 95% CI = 1.97-12.99) and diplotype A-C-A-G-G/A-C-A-G-G (OR = 21.08, 95% CI = 5.28-84.09) was also associated with the increased risk of HSCR, indicating a cumulative effect of these SNPs on the susceptibility of HSCR.ConclusionThese results support the hypothesis that common variations in RET pathway might play an important role in development of HSCR.

Highlights

Hirschsprung’s disease (HSCR) is a classic oligogenic disorder
The associations between the genotype and the risk of HSCR were estimated by odds ratios (ORs) and their 95% confidence interval (CI), which was calculated by unconditional logistic regression adjusted for gender
Subjects carrying the RET -5AA, -1CC, 135AA or 2307GG genotype had a 17.75-fold, 10.89-fold, 13.61-fold or 9.79-fold elevated risk for the development of HSCR, compared with the counterpart wild genotype, respectively

Summary

Methods

Study subjects This case-control study consisted of 123 sporadic HSCR (males: 75.6%) and 194 controls (males: 73.7%). Cases were histological diagnosed with either biopsy or surgical resection material for absence of enteric plexuses in Children’s Hospital Affiliated to Zhejiang University Medical School, among which twelve (10%) of patients were affected with long-segment aganglionosis (LSA) and the rest with short-segment aganglionosis (SSA). Controls were normal children taking physical examination in the same hospital during the same time period as the patients were enrolled and frequency matched to cases by sex and age. Both cases and controls were Chinese Han in Zhejiang and informed consent was obtained from their parents. Statistical analysis Chi-square test was used to compare the allele and genotype frequencies between cases and controls, as well as LSA and SSA. All of the statistical analyses were performed using Statistical Analysis System software (version 9.12; SAS Institute, Cary, NC)

Results

Background

Discussion