利用全基因體關聯性分析探討在台灣族群中調控血糖指數及血糖代謝相關罕見疾病之基因變異

TMUIR > College of Pharmacy > Master Program for Clinical Pharmacogenomics and Pharmacoproteomics > Dissertations/Theses > Item 987654321/62402

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Title:	利用全基因體關聯性分析探討在台灣族群中調控血糖指數及血糖代謝相關罕見疾病之基因變異 Using Genome-wide Association Study to Identify Genetic Variants for Blood Sugar Regulation and Glucose Metabolism Rare Diseases in a Taiwan population
Authors:	蔡承霖 TSAI, CHENG-LIN
Contributors:	臨床基因體學暨蛋白質體學碩士學位學程張偉嶠
Keywords:	第二型糖尿病;全基因組關聯性分析;空腹血糖;罕見疾病;年輕人成年型糖尿病;糖化血色素;Wolfram氏症候群 HbA1c;Wolfram Syndrome;Type 2 diabetes;Genome-wide association analysis;Fasting glucose;Rare diseases;Adult-onset diabetes in young adults
Date:	2022-06-29
Issue Date:	2022-12-29 11:09:24 (UTC+8)
Abstract:	第二型糖尿病 (T2D) 是一種以血糖長期升高為特徵的代謝疾病。第二型糖尿病經常導致許多併發症，更嚴重的是心血管疾病、中風和腎臟疾病。全球糖尿病患者人數逐年增加，2014年全球估計有4.22億成年人患有糖尿病。如何能夠早期預測糖尿病體質，進行必要的防治，已成為科學家研究的重要課題。全基因組關聯研究（GWAS）是指找出人類全基因組中是否存在單核?酸多態性（SNPs），並篩選出與疾病相關的SNPs。GWAS研究發現了許多以前未被發現的基因和染色體區域，為複雜疾病的發病機制提供了更多線索。過去有很多關於 GWAS 研究第二型糖尿病的文章，但沒有人對台灣人群進行過大數據研究。本研究是利用臺灣人體生物資料庫（TWB）提供的空腹血糖值與糖化血色素 ( HbA1c )和SNPs信息進行GWAS分析，尋找台灣人群中與血糖相關的SNPs。在這項研究中，我們在 TWB 中多致59,448 個樣本和 3,636,444 個 SNP 進行了 GWAS 分析。結果表明，在空腹血糖的GWAS分析中發現了39個顯著SNP。在 HbA1c 的 GWAS 分析中，發現了 35 個重要SNP。並且與至今已發表文章相比對，在空腹血糖中發現了4個以往沒有報導過的SNP (rs34874677、rs2074489、rs12922649和rs11650716）。對於 HbA1c，發現了一個以前未報告的 SNP (rs12037987)。另外值得一提的是，在HbA1c的GWAS結果中，可以發現rs7208565的P值非常顯著，值為5.07×10-363。結果顯示，血糖指標受多基因性調控。通過分析rs34874677的生理變化，推測它們可能影響血糖值。但在rs12922649、rs11650716、rs12037987和rs2074489中，並沒有直接的證據顯示與血糖的調控相關。此外使用 gnomAD 網站提供的等位基因頻率數據，發現 rs7208565在東亞族群中的頻率高於其他國家，因此我們推測 rs7208565 對於台灣HbA1c真的是會有影響。這種以GWAS分析台灣一般民眾針對空腹血糖及HbA1c連續變相所得到的相關SNP，是否在高血糖罕見疾病上依然也扮演一定的腳色呢？為了回答這個提問，我們結合前面這些顯著的74個SNP位點，針對高血糖罕見疾病的致病基因交叉分析，尋求交集，進一步探討這些SNP對於罕病致病機制上的貢獻。結果發現，在與罕見疾病與GWAS結果進行比對後，有三個疾病與GWAS結果有找到關聯性，分別是與年輕人成年型糖尿病2 (MODY2)相關的rs2971672、rs2971670與rs2908290、與MODY5相關的rs7501939以及與Wolfram氏症候群 ( Wolfram Syndrome )相關的rs9998835，並且解釋了在台灣基因體生物資料庫中的參與者會出現MODY2的可能性。雖然對於MODY5與Wolfram氏症候群的顯著因子仍位無法解釋，但是提供了未來在分析與研究中有了新的著點。 Type 2 diabetes (T2D) is a metabolic disease characterized by chronically elevated blood sugar. Type 2 diabetes often leads to many complications, more serious cardiovascular disease, stroke and kidney disease. The number of people with diabetes worldwide is increasing year by year, with an estimated 422 million adults worldwide living with diabetes in 2014. How to predict diabetes constitution early and carry out necessary prevention and treatment has become an important research topic for scientists. Genome-wide association study (GWAS) refers to finding out whether there are single nucleotide polymorphisms (SNPs) in the whole human genome and screening out disease-related SNPs. GWAS studies have uncovered many previously undiscovered genes and chromosomal regions, providing more clues about the pathogenesis of complex diseases. There have been many articles on GWAS research on type 2 diabetes in the past, but no one has done a big data study on the Taiwanese population. In this study, the fasting blood glucose, glycosylated hemoglobin (HbA1c) and SNPs information provided by the Taiwan Biobank (TWB) were used for GWAS analysis to search for blood sugar-related SNPs in the Taiwanese population. In this study, we performed GWAS analysis on more than 59,448 samples and 3,636,444 SNPs in TWB. The results showed that 39 significant SNPs were found in the GWAS analysis of fasting blood glucose. In the GWAS analysis of HbA1c, 35 significant SNPs were found. And compared with the published articles so far, 4 SNPs (rs34874677, rs2074489, rs12922649 and rs11650716) that have not been reported before were found in fasting blood glucose. For HbA1c, a previously unreported SNP (rs2074489) was found. It is also worth mentioning that in the GWAS results of HbA1c, it can be found that the P value of rs7208565 is very significant, with a value of 5.07×10-363. The results showed that blood glucose indicators were regulated by polygenicity. By analyzing the physiological changes of rs34874677, it is speculated that they may affect blood glucose values. However, in rs12922649, rs11650716 and rs2074489, there is no direct evidence that it is related to the regulation of blood sugar. In addition, using the allele frequency data provided by the gnomAD website, it was found that the frequency of rs7208565 in East Asian populations is higher than that in other countries, so we speculate that rs7208565 really has an impact on HbA1c in Taiwan. Does this kind of related SNPs obtained by GWAS analysis of Taiwanese general public for fasting blood sugar and HbA1c in continuous traits still play a certain role in the rare disease of hyperglycemia? In order to answer this question, we combined the above 74 significant SNP loci to cross-analyze the pathogenic genes of rare diseases of hyperglycemia, seek intersection, and further explore the contribution of these SNPs to the pathogenic mechanism of rare diseases. The results found that after comparing with rare diseases and GWAS results, three diseases were found to be associated with GWAS results. rs2971672, rs2971670 and rs2908290 were related to Maturity-onset Diabetes in Young Adults 2 (MODY2), rs7501939 was related to MODY5. rs9998835 was related to Wolfram Syndrome. Explains the likelihood that MODY2 will be present in participants in TWB. Although the significant factors for MODY5 and Wolfram Syndrome are still unexplained, we provides new points in analysis and research in the future.
Description:	碩士指導教授：張偉嶠委員：王紋璋委員：林炫沛委員：張偉嶠
Data Type:	thesis
Appears in Collections:	[Master Program for Clinical Pharmacogenomics and Pharmacoproteomics] Dissertations/Theses

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