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

ABSTRACT: BACKGROUND: Hirschsprung'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. METHODS: Genotypes 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. RESULTS: We 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. CONCLUSION: These results support the hypothesis that common variations in RET pathway might play an important role in development of HSCR.

SUBMITTER: Tou J

PROVIDER: S-EPMC3050791 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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

Tou Jinfa J Wang Li L Liu Li L Wang Ying Y Zhong Rong R Duan Shengyu S Liu Weiguang W Xiong Qixing Q Gu Qinglong Q Yang Hong H Li Hui H

BMC medical genetics 20110225

<h4>Background</h4>Hirschsprung'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.<h4>Methods</h4>Genotypes of -5G > A (rs10900296), -1A > C (rs10900297), c135G > A (rs1800858), c1296A > G (rs1 ...[more]

PMID: 21349203

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Project description:BACKGROUND: Hirschsprung disease (HSCR) is a complex disorder with traditional germline mutations in RET in up to 30% of familial cases and in 3% of sporadic cases in a population-based series. We have previously demonstrated that an ancestral haplotype at the 5' end of RET (haplotype 0) was strongly associated with a large subset of isolated HSCR cases and that a putative low penetrance susceptibility locus was encompassed within this ancestral haplotype, anchored by exon 2 SNP A45A. OBJECTIVE: To determine the 5' extent of the HSCR-associated ancestral haplotype by defining the linkage disequilibrium breakpoint in search for the low penetrance susceptibility locus. METHODS: Systematic screening of the region upstream of the anchoring A45A SNP, comprising RET intron 1, exon 1, and promoter in 117 population-based HSCR cases and 100 controls. Dual luciferase assay to determine differential activities between SNP combinations near a transcription start site. RESULTS: New SNP's were found which formed upstream haplotypes, anchored by A45A, in linkage disequilibrium with HSCR (2 = 76.96, p<0.00000001). Linkage disequilibrium appeared to break at the -1249C/T SNP. Further, the HSCR-associated genotype (00) was found in >60% of HSCR but only 2% of controls. Because only 2 variants, -200A>G and -196C>A, lie within the promoter region and are in proximity to the transcriptional start site (at -195), we modelled these combinations into constructs for luciferase reporter assay. The HSCR-associated SNP combination showed the lowest activity and the control-associated combination, the highest. CONCLUSIONS: Our observations seem to discard the existence of a HSCR-causing mutation as it is conceived in the traditional sense, but strengthen the idea of a specific combination of variants conferring susceptibility to the disease in a low penetrance fashion. The data derived from our functional "in vitro" studies would suggest that the HSCR-associated haplotype 0 may result in a lower level of expression of the RET gene [corrected]

Project description:BackgroundMany publications have evaluated the correlation between RET, PHOX2B polymorphisms and Hirschsprung's disease with conflicting results. We performed this meta-analysis to clarify the association of RET, PHOX2B polymorphisms with HSCR.MethodsWe searched Pubmed, Elsevier Science Direct, China National Knowledge Infrastructure database, Chinese Biomedical database, Google scholar. The combined odds ratio (OR) with 95% CI was calculated to estimate the strength of the association. Heterogeneity and publication bias were also assessed.ResultsIn total, 16 studies concerning RET and 4 studies concerning PHOX2B were included in the meta-analysis. The effects of five polymorphisms of RET (rs1800858, rs1800860, rs1800861, rs10900297, rs2435357) and one polymorphism (rs28647582) of PHOX2B were evaluated. We found a significant correlation between RET polymorphisms and HSCR. For rs1800858, the overall ORs (95% CI) of the A versus G, AA versus GG, AA/AG versus GG and AA versus GG/AG were 3.81 (2.28-6.35); 8.36 (3.45-20.25); 3.59 (1.83-7.02); and 6.60 (3.66-11.89). For rs1800861, the comparison of subjects in the G versus T, GG versus TT, GG/TG versus TT and GG versus TT/TG were 2.85(1.81-4.47); 5.38(2.68-10.80); 3.07(2.17-4.34) and 4.14(1.84-9.30) respectively. For rs10900297, the comparison results showed statistically significant. (OR(C versus A) = 5.05,95%CI = 4.16-6.13; OR(CC versus AA) = 9.73, 95%CI = 5.94-15.94; OR(CC/AC versus AA) = 5.31, 95%CI = 3.27-6.82; OR(CC versus AC/AA) = 7.06,95%CI = 5.60-8.91.) But, for rs1800860, the GG/GA versus AA did not reach statistical association (OR = 3.77, 95% CI = 0.94-15.07) and the G versus A, GG versus AA, GG versus GA/AA were 2.23 (1.60-3.11);4.56 (1.14-18.27); 2.38 (1.66-3.43) respectively. For rs2435357, the T versus C, TT versus CC, TT/TC versus CC and TT versus CC/TC were 4.53 (3.27-6.27); 11.44 (5.67-23.10); 4.04 (2.92-5.57), and 9.01(5.25-15.46).The single polymorphism of PHOX2B gene wasn't related to the risk for HSCR.ConclusionsThis meta-analysis shows a significant association between RET polymorphisms and HSCR.

Project description:BackgroundHirschsprung's disease, or congenital aganglionosis, is a developmental disorder of the enteric nervous system and is the most common cause of intestinal obstruction in neonates and infants. The disease has more than 80% heritability, including significant associations with rare and common sequence variants in genes related to the enteric nervous system, as well as with monogenic and chromosomal syndromes.MethodsWe genotyped and exome-sequenced samples from 190 patients with Hirschsprung's disease to quantify the genetic burden in patients with this condition. DNA sequence variants, large copy-number variants, and karyotype variants in probands were considered to be pathogenic when they were significantly associated with Hirschsprung's disease or another neurodevelopmental disorder. Novel genes were confirmed by functional studies in the mouse and human embryonic gut and in zebrafish embryos.ResultsThe presence of five or more variants in four noncoding elements defined a widespread risk of Hirschsprung's disease (48.4% of patients and 17.1% of controls; odds ratio, 4.54; 95% confidence interval [CI], 3.19 to 6.46). Rare coding variants in 24 genes that play roles in enteric neural-crest cell fate, 7 of which were novel, were also common (34.7% of patients and 5.0% of controls) and conferred a much greater risk than noncoding variants (odds ratio, 10.02; 95% CI, 6.45 to 15.58). Large copy-number variants, which were present in fewer patients (11.4%, as compared with 0.2% of controls), conferred the highest risk (odds ratio, 63.07; 95% CI, 36.75 to 108.25). At least one identifiable genetic risk factor was found in 72.1% of the patients, and at least 48.4% of patients had a structural or regulatory deficiency in the gene encoding receptor tyrosine kinase (RET). For individual patients, the estimated risk of Hirschsprung's disease ranged from 5.33 cases per 100,000 live births (approximately 1 per 18,800) to 8.38 per 1000 live births (approximately 1 per 120).ConclusionsAmong the patients in our study, Hirschsprung's disease arose from common noncoding variants, rare coding variants, and copy-number variants affecting genes involved in enteric neural-crest cell fate that exacerbate the widespread genetic susceptibility associated with RET. For individual patients, the genotype-specific odds ratios varied by a factor of approximately 67, which provides a basis for risk stratification and genetic counseling. (Funded by the National Institutes of Health.).

Dataset Information

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

Publications

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

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