Literature review: enteric nervous system development, genetic and epigenetic regulation in the etiology of Hirschsprung's disease.

Hirschsprung's disease (HSCR) is a developmental disorder of the enteric nervous system (ENS) derived from neural crest cells (NCCs), which affects their migration, proliferation, differentiation, or preservation in the digestive tract, resulting in aganglionosis in the distal intestine. The regulation of both NCCs and the surrounding environment involves various genes, signaling pathways, transcription factors, and morphogens. Therefore, changes in gene expression during the development of the ENS may contribute to the pathogenesis of HSCR. This review discusses several mechanisms involved in the development of ENS, confirming that deviant genetic and epigenetic patterns, such as DNA methylation, histone modification, and microRNA (miRNA) regulation, can contribute to the development of neurocristopathy. Specifically, the epigenetic regulation of miRNA expression and its relationship to cellular interactions and gene activation through various major pathways in Hirschsprung's disease will be discussed.

First trimester maternal vitamin D, ferritin, hemoglobin level and their associations with neonatal birthweight: Result from cohort study on vitamin D status and its impact during pregnancy and childhood in Indonesia.

INTRODUCTION: Vitamin D deficiency and anemia are examples of nutritional problems of global health significance. When these health issues effect pregnant women, they may become a threat to the fetus' potention for intrauterine growth. It has been known that the first trimester is the golden period of fetal programming which influences the fetuses and their life after birth. This study was aiming to analyze the association between first trimester maternal vitamin D, serum ferritin, hemoglobin level and neonatal birth weight. METHODS: From July 2016 a prospective cohort of pregnant women had been observed in four cities in West Java, Indonesia. Two hundred ninety four pregnant women were recuited in the first trimester and 203 of them had complete follow up until delivery. Collected data included maternal demography, blood analysis for ferritin, 25(OH) vitamin D in the first trimester of pregnancy and the birth weight of neonates. Associations were analyzed with multiple regression models. RESULTS: Vitamin D deficiency was highly prevalent among pregnant women in this study (approximately 75%) while anemia was found in 7.5 %, a little above the target of 5 %. However, no significant association was found between maternal serum vitamin D, serum ferritin, hemoglobin level in the first trimester and birth weight of the neonates, before and after adjustment for maternal age, pre-pregnancy body mass index, and parity. CONCLUSION: There were no associations found between vitamin D, ferritin, and hemoglobin level in the first trimester and neonatal birth weight. The negative results in this study should not diminish the benefit of nutritional supplementation during pregnancy. The possibility of other explanatory variables that influence these associations warrants further studies.

Fine mapping of the 9q31 Hirschsprung's disease locus.

Hirschsprung's disease (HSCR) is a congenital disorder characterised by the absence of ganglia along variable lengths of the intestine. The RET gene is the major HSCR gene. Reduced penetrance of RET mutations and phenotypic variability suggest the involvement of additional modifying genes in the disease. A RET-dependent modifier locus was mapped to 9q31 in families bearing no coding sequence (CDS) RET mutations. Yet, the 9q31 causative locus is to be identified. To fine-map the 9q31 region, we genotyped 301 tag-SNPs spanning 7 Mb on 137 HSCR Dutch trios. This revealed two HSCR-associated regions that were further investigated in 173 Chinese HSCR patients and 436 controls using the genotype data obtained from a genome-wide association study recently conducted. Within one of the two identified regions SVEP1 SNPs were found associated with Dutch HSCR patients in the absence of RET mutations. This ratifies the reported linkage to the 9q31 region in HSCR families with no RET CDS mutations. However, this finding could not be replicated. In Chinese, HSCR was found associated with IKBKAP. In contrast, this association was stronger in patients carrying RET CDS mutations with p = 5.10 x 10(-6) [OR = 3.32 (1.99, 5.59)] after replication. The HSCR-association found for IKBKAP in Chinese suggests population specificity and implies that RET mutation carriers may have an additional risk. Our finding is supported by the role of IKBKAP in the development of the nervous system.