應用次世代定序技術建立高三酸甘油脂血症基因檢測平台

Next-Generation sequencing to establish the genetic testing platform for hypertriglyceridemia

詹曉娟(Siao-Jyuan Jhan)

指導教授 ： 陳沛隆

國立臺灣大學/醫學院/分子醫學研究所/碩士(2021年)

https://doi.org/10.6342/NTU202104255

摘要

高三酸甘油酯血症是心血管和代謝疾病中常見的一種表型，其遺傳變異異常複雜。家族性乳糜微粒血症(familial chylomicronemia syndrome, FCS)導致的三酸甘油酯數值嚴重升高是由LPL、APOC2、APOA5、LMF1和GPIHBP1基因中的同型合子(homozygous)或雙等位基因功能喪失變異(biallelic loss-of-function variants)所引起。相比之下，多因素乳糜微粒血症(multifactorial chylomicronemia, MCM)則是由兩種不同類型的遺傳變異引起(1)罕見的雜合變異(heterozygous variants)在家族性乳糜微粒血症的五個基因中具有可變外顯率(variable penetrance)(2)常見變異點位(common variants)，其個別單核苷酸多型性(Single Nucleotide Polymorphism, SNP)小效應積累使得三酸甘油脂升高，其複雜的遺傳變異因素造成臨床上分子檢測極大的困難與挑戰。有鑑於此，本研究建立次世代定序平台篩檢高三酸甘油酯血症之變異類型及釐清複雜的遺傳因素，在次世代定序與傳統的定序方法相較之下，能夠同時讀取上百萬條DNA序列，所以可以大量降低成本，且快速幫助病患確立基因變異找出原因，了解本土病患的基因變異分佈情形，則未來應考慮包括(1)評估特定類型的高三酸甘油酯血症遺傳易感性是否影響醫療決策或長期結果(2)探討其它遺傳因素，包括全基因組多基因評分、新基因或基因與基因-環境之間的相互作用，以擴展我們對高三酸甘油酯血症的了解。

關鍵字

高三酸甘油酯血症 ； 次世代定序 ； 基因檢測 ； 遺傳決定因素 ； 單基因 ； 多基因 ； 家族性乳糜微粒血症 ； 多因素乳糜微粒血症

並列摘要

Hypertriglyceridemia is a common phenotype in cardiovascular and metabolic diseases, and its genetic variation is very complex. Severe increases hypertriglyceridemia caused from familial chylomicronemia syndrome (FCS) are caused by homozygous variants or biallelic loss-of-function variants in the LPL,APOC2,APOA5,LMF1 and GPIHBP1 genes. The susceptibility multifactorial chylomicronemia (MCM) is caused different types of genetic variations:(1) the rare variant heterozygous variants (2) common variants in five genes of FCS, its individual accumulation of small effects increases TG, and its complex genetic variation factors make clinical molecular detection extremely difficult and challenging. This study establishes a next-generation sequencing platform to screen for the types of mutations and to clarify complex genetic factors for hypertriglyceridemia ,compared with traditional sequencing methods, NGS can read millions of DNA sequences at the same time, so it can greatly reduce costs, and quickly help patients to establish gene mutations, find out the causes, and understand the distribution of gene mutations in local patients situation, and to consider in the future : assessing whether the genetic susceptibility of specific types of high triglycerides affects medical decision-making or long-term outcomes. Other genetic factors, including genome-wide polygene scores, new genes or differences between genes and the environment, to expand the understanding of the attributes of Hypertriglyceridemia.

並列關鍵字

Hypertriglyceridemia ； Next-generation sequencing ； genetic testing ； single genes ； genetic determinants ； familial chylomicronemia syndrome(FCS) ； multifactorial chylomicronemia (MCM)

參考文獻

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