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

ABSTRACT: 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.

SUBMITTER: Musthofa F

PROVIDER: S-EPMC5641765 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Project description:Hirschsprung disease (HSCR), which may be sporadic or familial, occurs in 1:5000 live births and presents with functional intestinal obstruction secondary to aganglionosis of the hindgut. Germline mutations of the RET proto-oncogene are believed to account for up to 50% of familial cases and up to 30% of isolated cases in most series. However, these series are highly selected for the most obvious and severe cases and large familial aggregations. Population based studies indicate that germline RET mutations account for no more than 3% of isolated HSCR cases. Recently, we and others have noted that specific polymorphic sequence variants, notably A45A (exon 2), are over-represented in isolated HSCR.In order to determine if it is the variant per se, a combination thereof, or another locus in linkage disequilibrium which predisposes to HSCR, we looked for association of RET haplotype(s) and disease in HSCR cases compared to region matched controls.Seven loci across RET were typed and haplotypes formed for HSCR cases, their unaffected parents, and region matched controls. Haplotype and genotype frequencies and distributions were compared among these groups using the transmission disequilibrium test and standard case-control statistic.Twelve unique haplotypes, labelled A-L, were obtained. The distributions of haplotypes between cases and controls (chi(11)(2) =81.4, p<<0.0001) and between cases and non-transmitted parental haplotypes were significantly different (chi(2)(11)=53.1, p<0.0001). Genotypes comprising pairs of haplotypes were formed for cases and controls. There were 38 different genotypes among cases and controls combined. Inspection of the genotypes in these two groups showed that the genotype distribution between cases and controls was distinct (chi(37)(2)=93. 8, p<<0.0001). For example, BB, BC, BD, and CD, all of which contain at least one allele with the polymorphic A45A, are prominently represented among HSCR cases, together accounting for >35% of the case genotypes, yet these four genotypes were not represented among the population matched normal controls. Conversely, AA, AG, DD, GG, and GJ, none of which contains A45A, are commonly represented in the controls, together accounting for 43% of the control genotypes, and yet they are never seen among the HSCR cases.Our data suggest that genotypes comprising specific pairs of RET haplotypes are associated with predisposition to HSCR either in a simple autosomal recessive manner or in an additive, dose dependent fashion.

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

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