2012-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/649456摘要：新生兒黃膽是一個常困擾父母及小兒科醫師的常見的問題。一般而言，亞洲足月兒的黃膽最高值約是高加索人和黑人的兩倍。這代表可能有基因的因素參與了新生兒黃膽的發生。除了基因變異，外基因的變化(epigenetic change)也和人類疾病的發生有關，特別是在DNA合成最快速的新生兒時期。目前已知一些和內分泌相關的代謝性疾病，例如母親高血糖、低adiponectin血清濃度、和高alpha-fetoprotein血清濃度，和新生兒黃膽有關。但是，這些外在環境(母體環境)所導致外基因的變異和新生兒黃膽之間的關聯則未被深入研究過。在我們先前的研究中發現，約有22% (151/688) 的新生兒有黃膽過高而需要治療，有48.5% (334/688)的新生兒有UGT1A1基因異常，而純母乳哺育的新生兒，其高黃疸比率更高達 27% (91/341)。在這些純母乳哺育的新生兒若其UGT1A1基因的 Gly71Arg有變異的話，會發生高黃膽的機會是正常新生兒的 2-13倍。不過在354個UGT1A1基因正常的新生兒，仍有 20% (70/354) 的新生兒會發生高黃疸血症，其原因目前仍不清楚。此外，我們初步分析各6位control及黃膽病人全基因組 DNA methylation的結果，顯示有149 個基因的 DNA methylation status 是有明顯改變的,包括和調控膽紅素代謝或膽汁排泄的 HMGN1, GIP, GCK, ZNF222, ZNF581, CYBB, PTHLH, VPS5 and JAG1.因此，在這個研究中，我們希望利用 high-throughput genome-wide SNP genotyping 和外基因變異的研究的方式，來找尋和新生兒黃膽有關聯的基因和訊息路徑。因此本研究的目標有:1. 建立一個大型的新生兒黃膽研究資料庫。2. 針對新生兒黃膽進行母親血液 adiponectin及AFP, 以及新生兒的UGT1A1, G6PD, OATP1B1, Ho-1多型異構性基因分析，以找出和新生兒黃膽和延遲性新生兒黃膽的相關基因。3. 針對新生兒黃膽進行全基因組 DNA methylation 分析，以期發現和新生兒黃膽相關的基因活動，證實並找出和新生兒黃膽相關的訊息路徑。我們預期將藉由這個研究，找出一套篩選出新生兒黃膽的高危險群的模式，並期待藉由此模式，能減少或預防嚴重的新生兒黃疸，進而減少因新生兒黃疸入院所引起的社會成本增加，以及父母及兒科醫師因此問題所引發的焦慮。<br> Abstract: Neonatal hyperbilirubinemia is the most common clinical condition in the newborn that requires evaluation and management1 and the most frequent reason for hospital readmission during the first week of postnatal life. An imbalance between the production and elimination of bilirubin results in various level of hyperbilirubinemia in every neonate. The peak serum levels of unconjugated bilirubin in full-term Asian (Japanese, Korean, or Chinese) and American Indian neonates are double those in Caucasian and black populations. This finding suggests that genetic factors are involved in the development of neonatal hyperbilirubinemia.Recently, homozygous A(TA)7TAA variation in promoter of UGT1A1 gene was found to be associated with neonatal hyperbilirubinemia in Sephardic Jews, Americans, Italians, and British. However, in Japanese and Taiwanese studies, the high allele-frequency of Gly71Arg, but not promoter polymorphism, in UGT1A1 gene was found to be responsible for neonatal hyperbilirubinemia. These reports reveal that the relationship between the site of variant UGT1A1 gene and neonatal hyperbilirubinemia may differ among races.Besides gene variants, the epigenetic process is also an important regulation in human diseases especially during neonatal development because the DNA synthetic rate is high. Some endocrine metabolic disorders have also been reported to correlate with neonatal hyperbilirubinemia, such as maternal hyperglycemia, low serum adiponectin levels, and elevated serum alpha-fetoprotein (AFP) levels. However, the epigenetic mechanism between environmental exposure and neonatal hyperbilitubinemia is unknown.In our previous study, we found in those pure breast-fed neonates, those who has Gly71Arg in UGT1A1 gene has higher incidence of hyperbilirubinemia (OR: 2.1 for heterozygous and 12.9 for homozygous). This indicates there is gene-enviromental interaction in the pathogenesis of neonatal hyperbilirubinemia. In addition, we primarily analyzing genowide DNA methylation status between 6 controls and 6 cases with hyperbilirubinemia and found mean methylation levels for 149 genes including HMGN1, GIP, GCK, and JAG1 were found significantly increased in hyperbilirubinemia infants then in control infants. Besides, infants with hyperbilirubinemia showed hypomethylation changes of genes including ZNF222, ZNF581, CYBB, PTHLH, and VPS53.In this sub-project, we would like to do high-throughput genome-wide SNP genotyping and epigenetic analysis to identify the candidate genes that contribute to neonatal hyperbilirubinemia. The specific aims for this sub-project include:Aim 1: To establish the large data base of neonatal hyperbilirubinemia including clinical course and complete follow-up.Aim 2: To analyze the maternal adiponectin & APF levels, SNP genotying of UGT1A1, G6PD, OATP1B1, and Ho-1 genes and its association with neonatal hyperbilirubinemia and prolong neonatal hyperbilirubinemia.Aim 3: To do genome-wide analysis of DNA methylation first and validate the candidate genes or pathways which determine the susceptibility of neonatal hyperbilirubinemia in our population.This sub-project will help us to identify the genetic factors that are correlated neonatal hyperbilirubinemia. If we can setup the predict model to identify the high risk group, we can decrease the incidence of neonatal hyperbilirubinemia by early and aggressive intervention, and decrease the hospitalization fee in these neonates.