Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

AB099. Joint effects of RET and SEMA3 polymorphisms in Hirschsprung disease

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.

SUBMITTER: Santiko W

PROVIDER: S-EPMC5641808 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Population variation in total genetic risk of Hirschsprung disease from common RET, SEMA3 and NRG1 susceptibility polymorphisms.

Project description:The risk of Hirschsprung disease (HSCR) is ∼15/100 000 live births per newborn but has been reported to show significant inter-individual variation from the effects of seven common susceptibility alleles at the RET, SEMA3 and NRG1 loci. We show, by analyses of these variants in 997 samples from 376 HSCR families of European ancestry, that significant genetic risk can only be detected at RET (rs2435357 and rs2506030) and at SEMA3 (rs11766001), but not at NRG1. RET rs2435357 also showed significant frequency differences by gender, segment length of aganglionosis and familiality. Further, in combination, disease risk varied >30-fold between individuals with none and up to 6 susceptibility alleles. Thus, these polymorphisms can be used to stratify the newborn population into distinct phenotypic classes with defined risks to understand HSCR etiology.

| S-EPMC4406299 | biostudies-literature

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

Project description:BackgroundHirschsprung 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.MethodsSixty 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.ResultsRET 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.ConclusionsRET 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.

| S-EPMC4258000 | biostudies-literature

Effects of RET, NRG1 and NRG3 Polymorphisms in a Chinese Population with Hirschsprung Disease.

Project description:The RET proto-oncogene was identified as a major locus involved in Hirschsprung disease (HSCR). A genome-wide association study (GWAS) and whole exome sequencing identified NRG1 and NRG3 as additional HSCR susceptibility loci. We investigated the effects of RET (rs2506030 and rs2435357), NRG1 (rs2439302, rs16879552 and rs7835688) and NRG3 (rs10748842, rs10883866 and rs6584400) polymorphisms in a Chinese population with HSCR. We assessed single nucleotide polymorphisms (SNPs) in the RET, NRG1 and NRG3 genes in a cohort of 362 sporadic HSCR patients and 1,448 normal controls using a TaqMan genotyping assay. Significant associations were found between HSCR risk and rs2506030, rs2435357, rs2439302 and rs7835688 (odds ratio [OR] 1.64, P = 1.72E-06; 2.97, P = 5.15E-33; 1.84, P = 9.36E-11; and 1.93, P = 1.88E-12, respectively). Two locus analyses of SNPs indicated increased disease risks of HSCR between NRG1 rs2439302 and RET rs2435357 or rs2506030. RET rs2506030 (GG genotype) and rs2435357 (TT genotype), in combination with NRG1 rs2439302 (GG genotype), were strongly associated with the highest risk of HSCR (OR = 56.53, P = 4.50E-07) compared with the two loci or a single SNP of either RET or NRG1. Our results support the association between genetic variation of RET and NRG1 and susceptibility to HSCR in the Chinese population.

| S-EPMC5335705 | biostudies-literature

Multiple, independent, common variants at RET, SEMA3 and NRG1 gut enhancers specify Hirschsprung disease risk in European ancestry subjects.

Project description:PurposeHirschsprung disease (HSCR) is a developmental disorder of the enteric nervous system (ENS) characterized by congenital aganglionosis arising from coding variants in ENS genes causing partial or total loss-of-function. Low-penetrance, common, noncoding variants at RET, SEMA3 and NRG1 loci are also associated with HSCR, with small-to-moderate loss of gene expression mediated through sequence variants in cis-regulatory elements (CRE) as another causal mechanism. Since these latter variants are common, many individuals carry multiple risk variants. However, the extent and combinatorial effects of all putative CRE variants within and across these loci on HSCR is unknown.MethodsUsing 583 HSCR subjects, one of the largest samples of European ancestry studied, and genotyping 56 tag variants, we evaluated association of all common variants overlapping putative gut CREs and fine-mapped causal variants at RET, SEMA3 and NRG1.ResultsWe demonstrate that 28 and 8 tag variants, several of which are genetically independent, overlap putative-enhancers at the RET and SEMA3 loci, respectively, as well as two fine-mapped tag variants at the NRG1 locus, are significantly associated with HSCR. Importantly, disease risk increases with increasing numbers of risk alleles from multiple variants within and across these loci, varying >25-fold across individuals.ConclusionThis increasing allele number-dependent risk, we hypothesize, arises from HSCR-relevant ENS cells sensing the reduced gene expression at multiple ENS genes since their developmental effects are integrated through gene regulatory networks.

| S-EPMC8526751 | biostudies-literature

AB097. Combined effects of RET transcriptional enhancer variants in Hirschsprung disease

Project description:Background Hirschsprung disease (HSCR) is a complex genetic disorder, which characterized by absence of ganglion cells along variable lengths of the intestines in neonates, with the RET was identified as a major locus involved in HSCR. In this study, we investigated the joint effects of common variants within the RET transcriptional enhancer, rs2435357 and rs2506030, for development of HSCR in Indonesia. Methods Sixty HSCR patients and 122 non-HSCR controls was involved in this study. Two genetic markers of the RET were examined using TaqMan assay. We analyzed the case-control association tests between two genetic markers and HSCR using the statistic. A P value <0.025 is considered significant given that two tests (markers) were performed in the analysis. Results There was high correlation between RET rs2435357 marker and HSCR either by case-control analysis (OR =4.46, P=2.5×10?8) or transmission disequilibrium test (TDT, P=4.2×10?6), but not RET rs2506030 (OR =1.68, P=0.042 and P=0.034, respectively). Two locus analyses of variants revealed that RET rs2435357 (TT), in combination with rs2506030 (GG), were associated with the increased disease risks of HSCR (OR =5.42, P=3.9×10?6) compared with a single variant of rs2506030. Conclusions Our study shows that RET rs2435357 variant is a strong genetic risk factors for development of HSCR in Indonesia. In addition, the disease effects of RET rs2506030 genotypes are crucially dependent on the effects of rs2435357 genotypes.

| S-EPMC5641765 | biostudies-literature

Whole genome sequencing reveals epistasis effects within RET for Hirschsprung disease.

Project description:Common variants in RET and NRG1 have been associated with Hirschsprung disease (HSCR), a congenital disorder characterised by incomplete innervation of distal gut, in East Asian (EA) populations. However, the allelic effects so far identified do not fully explain its heritability, suggesting the presence of epistasis, where effect of one genetic variant differs depending on other (modifier) variants. Few instances of epistasis have been documented in complex diseases due to modelling complexity and data challenges. We proposed four epistasis models to comprehensively capture epistasis for HSCR between and within RET and NRG1 loci using whole genome sequencing (WGS) data in EA samples. 65 variants within the Topologically Associating Domain (TAD) of RET demonstrated significant epistasis with the lead enhancer variant (RET+3; rs2435357). These epistatic variants formed two linkage disequilibrium (LD) clusters represented by rs2506026 and rs2506028 that differed in minor allele frequency and the best-supported epistatic model. Intriguingly, rs2506028 is in high LD with one cis-regulatory variant (rs2506030) highlighted previously, suggesting that detected epistasis might be mediated through synergistic effects on transcription regulation of RET. Our findings demonstrated the advantages of WGS data for detecting epistasis, and support the presence of interactive effects of regulatory variants in RET for HSCR.

| S-EPMC9705416 | biostudies-literature

Identifying candidate Hirschsprung disease-associated RET variants.

Project description:Patients with sporadic Hirschsprung disease (HSCR) show increased allele sharing at markers in the 5' region of the RET locus, indicating the presence of a common ancestral RET mutation. In a previous study, we found a haplotype of six SNPs that was transmitted to 55.6% of our patients, whereas it was present in only 16.2% of the controls we used. Among the patients with that haplotype, 90.8% had it on both chromosomes, which led to a much higher risk of developing HSCR than when the haplotype occurred heterozygously. To more precisely define the HSCR-associated region and to identify candidate disease-associated variant(s), we sequenced the shared common haplotype region from 10 kb upstream of the RET gene through intron 1 and exon 2 (in total, 33 kb) in a patient homozygous for the common risk haplotype and in a control individual homozygous for the most common nonrisk haplotype. A comparison of these sequences revealed 86 sequence differences. Of these 86 variations, 8 proved to be in regions highly conserved among different vertebrates and within putative transcription factor binding sites. We therefore considered these as candidate disease-associated variants. Subsequent genotyping of these eight variants revealed a strong disease association for six of the eight markers. These six markers also showed the largest distortions in allele transmission. Interspecies comparison showed that only one of the six variations was located in a region also conserved in a nonmammalian species, making it the most likely candidate HSCR-associated variant.

| S-EPMC1199373 | biostudies-literature

AB087. Synergistic genetic effects of RET and NRG1 susceptibility variants in Hirschsprung disease

Project description:Background Hirschsprung disease (HSCR) is a complex genetic disorder, which characterized by absence of ganglion cells along variable lengths of the intestines in neonates, with the RET and NRG1 are reported as the most common susceptible genes for HSCR development. Here, we investigated three common genetic markers: RET rs2506030 and NRG1 rs7835688 and rs16879552, to determine their potential interactions to the susceptibility of HSCR in Indonesian population. Methods We ascertained 60 HSCR subjects and 118 non-HSCR controls. Three genetic markers of the RET and NRG1 were examined using TaqMan assay. Case-control association tests between three genetic markers and HSCR were performed using the ?2 (chi square) statistic and 2×2 contingency tables. We analyzed the family based association in duos and trios using the transmission disequilibrium test (TDT) for the variants using PLINK. Results There was association between NRG1 rs7835688 (4.3×10?3) variant and HSCR, but not RET rs2506030 (P=0.042) and NRG1 rs16879552 (P=0.097). TDT of 33 HSCR families demonstrates no genetic effect either at RET rs2506030 (P=0.034) or NRG1 rs7835688 (P=0.18) and rs16879552 (P=0.28). Two locus analyses of polymorphisms demonstrated that RET rs2506030 (GG), in combination with NRG1 rs7835688 (CC) or rs16879552 (CC), were associated with the increased disease risks of HSCR (OR =6.22, P=0.028 and OR =3.34, P=6.0×10?4, respectively) compared with a single variant of either RET or NRG1. Conclusions Our study shows that RET and NRG1 polymorphisms are common genetic risk factors for Indonesian HSCR. These results also imply that synergistic effects of RET and NRG1 is necessary for normal ganglionosis.

| S-EPMC5641813 | biostudies-literature

RET somatic mutations are underrecognized in Hirschsprung disease.

Project description:PurposeWe aimed to determine the frequency of RET mosaicism in Hirschsprung disease (HSCR), test whether it has been underestimated, and to assess its contribution to HSCR risk.MethodsTargeted exome sequencing (n = 83) and RET single-gene screening (n = 69) were performed. Amplicon-based deep sequencing was applied on multiple tissue samples. TA cloning and sequencing were conducted for validation.ResultsWe identified eight de novo mutations in 152 patients (5.2%), of which six were pathogenic mosaic mutations. Two of these patients were somatic mosaics, with mutations detected in blood, colon, and saliva (mutant allele frequency: 35-44%). In addition, germ-line mosaicism was identified in four clinically unaffected subjects, each with an affected child, in multiple tissues (mutant allele frequency: 1-28%).ConclusionSomatic mutations of the RET gene are underrecognized in HSCR. Molecular investigation of the parents of patients with seemingly sporadic mutations is essential to determine recurrence risk in these families.

| S-EPMC7814876 | biostudies-literature

Genotyping analysis of 3 RET polymorphisms demonstrates low somatic mutation rate in Chinese Hirschsprung disease patients.

Project description:BackgroundGenetic mosaicism has been reported for both coding and non-coding sequences in the RET gene in Hirschsprung disease (HSCR) patients. This study aimed to investigate somatic mutation rate in Chinese population by comparing both homozygous genotype percentage and risk allele frequency of 3 RET single nucleotide polymorphisms (SNPs) among blood and colon samples.MethodsDNA was extracted from 59 HSCR blood samples, 59 control blood samples and 76 fresh frozen colon tissue samples (grouped into ganglionic, transitional and aganglionic level). Genotype status of rs2435357 and rs2506030 was examined by competitive allele specific hydrolysis probes (Taqman) PCR technology, and rs2506004 was examined by Sanger sequencing. Homozygous genotype percentage and risk allele frequency were calculated for each type of sample and compared by chi-square test. P<0.05 was regarded as being statistically significant.ResultsColon tissue DNA samples showed similar frequency of SNPs as that of the blood DNA samples in HSCR patients, both of which are significantly higher than the control blood group (rs2435357 TT genotype: 71.2%, 74.7% versus 22.0% in HSCR blood, HSCR colon and control blood DNA respectively, P=0.000; rs2506004 AA genotype: 72.4%, 83.1% versus 25.5%, P=0.000; rs2506030 GG genotype: 79.7%, 77.2% versus 54.2%, P=0.000 and 0.004). With respect to DNA extracted from ganglionic, transitional and aganglionic levels, no statistically significant difference was demonstrated in those 3 regions (rs2435357: P=0.897; rs2506004: P=0.740; rs2506030: P=0.901).ConclusionOur data does not support the notion that high frequency of somatic changes as an underlying etiology of Chinese HSCR population.

| S-EPMC4503131 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data