Association of genetic polymorphisms in the RET-protooncogene and NRG1 with Hirschsprung disease in Thai patients

Phusantisampan, Theerawut; Sangkhathat, Surasak; Phongdara, Amornrat; Chiengkriwate, Piyawan; Patrapinyokul, Sakda; Mahasirimongkol, Surakameth

doi:10.1038/jhg.2012.18

Cited by 39 publications

(51 citation statements)

References 27 publications

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“…These authors also demonstrated significant statistical evidence of genetic interaction between the RET rs2435357 and NRG1 rs7835688 variants, increasing the overall risk a further 2.3-fold, specifically in the presence of RET TT and NRG1 CG genotypes. Other authors have also reported genetic interactions between RET and NRG1 for both rare [10] and common [11] variants although the statistical significance of these findings is true only for common variants. These results are reminiscent of the individually strong genetic effects and interactions between loss-of-function alleles at RET and EDNRB , the two major signaling pathways important to enteric nervous system (ENS) development [12].…”

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confidence: 99%

Effects of RET and NRG1 polymorphisms in Indonesian patients with Hirschsprung disease

Gunadi

Kapoor

Ling

et al. 2014

Journal of Pediatric Surgery

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Background Hirschsprung disease (HSCR) is a neurocristopathy characterized by absence of intramural ganglion cells along variable lengths of the gastrointestinal tract in neonates. Three polymorphisms, rs2435357, within a conserved transcriptional enhancer of RET, and, rs7835688 and rs16879552, within intron 1 of NRG1, have been shown to be associated with isolated forms of HSCR. We wished to replicate these findings, and study the interactions between these variants, in Indonesian HSCR patients. Methods Sixty isolated HSCR patients and 124 controls were ascertained for this study. The three genetic markers were examined using TaqMan Genotyping Assays in genomic DNA for association studies. Results RET rs2435357 showed the strongest association with HSCR both by case–control analysis (p = 2.5 × 10−8) and transmission disequilibrium test (p = 4.2 × 10−6). NRG1 rs7835688 was modestly associated with HSCR only by case–control analysis (p = 4.3 × 10−3), whereas rs16879552 demonstrated no association (p > 0.097). Two locus analyses of variants showed significant interactions with increased and decreased disease risks of HSCR at NRG1 but conditional on rs2435357 genotype. Conclusions RET and NRG1 variants are common susceptibility factors for HSCR in Indonesia. These common variants demonstrate that development of HSCR requires joint effects of RET and NRG1 early in gut development.

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confidence: 99%

Effects of RET and NRG1 polymorphisms in Indonesian patients with Hirschsprung disease

Gunadi

Kapoor

Ling

et al. 2014

Journal of Pediatric Surgery

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“…Interestingly, the frequency of this NRG1 rare variant found in Indonesian [1/54 (1.8%) patients] was similar to those of Caucasian and Chinese probands [3/207 (1.4%) and 13/358 (3.6%) patients, respectively; with p = 0.45] [10, 11]. Furthermore, the NRG1 rs7835688 common variant was originally associated with HSCR in Chinese patients [9] and has been similarly observed in other Asian ancestry cases [4, 27], but these associations were not replicated in any Caucasian population [11, 28]. …”

Section: Discussionmentioning

confidence: 56%

“…Although there have been previous studies correlating NRG1 SNPs with disease association in HSCR, these have only been reported in three populations, namely Chinese, Caucasian, and Thais [10, 11, 27, 28]. Indeed, contrary to the findings in Chinese, Luzón-Toro et al [11] failed to find association of NRG1 variants with HSCR phenotype in Spanish patients and suggested that this could be due to population differences.…”

Section: Discussionmentioning

confidence: 94%

“…Indeed, contrary to the findings in Chinese, Luzón-Toro et al [11] failed to find association of NRG1 variants with HSCR phenotype in Spanish patients and suggested that this could be due to population differences. In the Thai patients, only four NRG1 SNPs were selected for association studies and disease correlation was found in Thai-Chinese but not Thai-Muslim patients suggesting ethnicity differences [27]. Our present study is unique in this being a comprehensive screen of NRG1 gene in Indonesian HSCR patients.…”

Section: Discussionmentioning

confidence: 99%

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NRG1 variant effects in patients with Hirschsprung disease

et al. 2018

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BackgroundHirschsprung disease (HSCR) is a heterogeneous genetic disorder characterized by absence of ganglion cells along the intestines resulting in functional bowel obstruction. Mutations in neuregulin 1 (NRG1) gene have been implicated in some cases of intestinal aganglionosis. This study aims to investigate the contribution of the NRG1 gene to HSCR development in an Indonesian population.MethodsWe analyzed the entire coding region of the NRG1 gene in 54 histopathologically diagnosed HSCR patients.ResultsAll patients were sporadic non-syndromic HSCR with 53/54 (98%) short-segment and 1/54 (2%) long-segment patients. NRG1 gene analysis identified one rare variant, c.397G > C (p.V133 L), and three common variants, rs7834206, rs3735774, and rs75155858. The p.V133 L variant was predicted to reside within a region of high mammalian conservation, overlapping with the promoter and enhancer histone marks of relevant tissues such as digestive and smooth muscle tissues and potentially altering the AP-4_2, BDP1_disc3, Egr-1_known1, Egr-1_known4, HEN1_2 transcription factor binding motifs. This p.V133 L variant was absent in 92 non-HSCR controls. Furthermore, the rs7834206 polymorphism was associated with HSCR by case–control analysis (p = 0.037).ConclusionsThis study is the first report of a NRG1 rare variant associated with HSCR patients of South-East Asian ancestry and provides further insights into the contribution of NRG1 in the molecular genetic pathogenesis of HSCR.Electronic supplementary materialThe online version of this article (10.1186/s12887-018-1265-x) contains supplementary material, which is available to authorized users.

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“…Genotype determination of the SNP rs16754, a synonymous SNP within exon 7, was performed using the TaqMan SNP genotyping system (Applied Biosystems, Foster City, CA, USA) ( Table I). The details of this method were previously reported (23). The assay mixes, including unlabeled polymerase chain reaction (PCR) primers, carboxyfluorescein (FAM) and VIC dye-labeled TaqMan minor groove binder probes of the Assays-by-Design system, were designed by Applied Biosystems.…”

Section: Patients and Controlsmentioning

confidence: 99%

Association of Wilms' tumor 1 gene single-nucleotide polymorphism rs16754 with colorectal cancer

Sangkhathat

Maneechay

Chaiyapan

et al. 2015

Molecular and Clinical Oncology

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Abstract. Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide. Our recent study demonstrated that the expression of Wilms' tumor 1 gene (WT1) is associated with surgical outcome in CRC patients. The present study aimed to investigate the genetic association of the single-nucleotide polymorphism rs16754 in the WT1 gene with the occurrence of CRC, using an age-matched case-control study design. In addition, the correlation between genotype and WT1 expression was investigated. Genomic DNA samples from 104 CRC cases, aged 15-65 years, and 208 healthy controls, were genotyped for rs16754 using the TaqMan genotyping method. The genotype distribution conformed to the Hardy-Weinberg equilibrium (P=0.80). The overall minor allele frequency (MAF) of rs16754 (allele A) was 0.33. The MAF among CRC cases was significantly higher compared with that in controls (0.39 vs. 0.31, respectively; P=0.03). The AA genotype was significantly associated with the disease (odds ratio = 2.51, 95% confidence interval: 1.24-5.07, P=0.01). Cases with the AA genotype exhibited a significantly poorer 3-year overall survival (60%), compared with those with the GG or GA genotypes (80%) (log-rank test, P<0.01). Reverse transcription quantitative polymerase chain reaction analysis demonstrated that the expression of WT1 in tumor tissues was higher compared with that in normal tissue; however, there were no significant differences in its expression among different genotypes. Therefore, rs16754 was found to be associated with the occurrence and prognosis of CRC in our subjects.

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Association of genetic polymorphisms in the RET-protooncogene and NRG1 with Hirschsprung disease in Thai patients

Cited by 39 publications

References 27 publications

Effects of RET and NRG1 polymorphisms in Indonesian patients with Hirschsprung disease

Effects of RET and NRG1 polymorphisms in Indonesian patients with Hirschsprung disease

NRG1 variant effects in patients with Hirschsprung disease

Association of Wilms' tumor 1 gene single-nucleotide polymorphism rs16754 with colorectal cancer

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