Taipei Medical University Institutional Repository:Item 987654321/58795
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    题名: 利用全基因體關聯性分析探討在臺灣族群中影響腎功能表徵之特異基因變異
    Using Genome-wide Association Study to Identify the Specific Genetic Variants for Kidney Function-related Traits in Taiwanese Population
    作者: 陳盈君
    Chen, Ying-Chun
    贡献者: 臨床藥物基因體學暨蛋白質體學碩士學位學程
    吳麥斯
    張偉嶠
    关键词: 全基因體關聯性研究;候選基因策略;腎絲球過濾率;糖尿病腎病變;基因變異;基因易感性
    Genome-wide association study;candidate gene approach;estimated glomerular filtration rate;diabetic kidney disease;genetic variants;genetic susceptibility
    日期: 2019-07-04
    上传时间: 2020-02-25 12:35:06 (UTC+8)
    摘要: Kidney disease is a global public health issue associated with huge economic burden. Chronic kidney disease contributes to increased risks of cardiovascular complications, mortality, and end-stage renal disease (ESRD). The incidence and prevalence rates of ESRD in Taiwan remained the highest worldwide according to 2018 USRDS ADR. The assessment of genetic factors influencing kidney function among specific population has substantial clinical relevance. We therefore conducted two divided studies using 1) a genome-wide approach to identify genetic loci for kidney function-related traits in Taiwanese general population; 2) a candidate gene approach to investigate risk variants in diabetic kidney disease (DKD) patients.
    In the first part of our study, we investigated the association of genetic factors with the levels of the estimated glomerular filtration rate (eGFR) using a population-based genome-wide approach. The quality control filtering and genotype imputation yield 10,008 Taiwan biobank participants and 6,553,511 variants for final analyses. Our results revealed one significant locus (4q21.1) and three suggestive significant loci (17q23.2, 22q13.2 and 3q29) for eGFR in Taiwanese population. A total of four conditional-independent single-nucleotide polymorphisms were identified as the most important variants within these regions, including rs55948430 (CCDC158), rs1010269 (BCAS3), rs56108505 (MKL1) and rs34796810 (upstream of DLG1). By performing meta-analysis, we found that the 4q21.1 and 17q23.2 loci were successfully replicated in European population, whilst only 17q23.2 locus was replicated in African American ancestry. Therefore, while the above two are suggested as transethnic loci, the other two loci (22q13.2 and 3q29) are candidates for further validation and functional analyses. They may contribute in regulating kidney function among Taiwanese and East Asian-specific populations.
    The second part among DKD patients, we conducted a follow-up genotyping study based on our previous transcriptomic investigation. The candidate gene UBE3C is implicated in ubiquitination proteasome system (UPS) pathway, which plays a potential role in the progression of DKD. A total of 263 patients were included in the final analyses, comprising 172 cases included DM patients with CKD and 91 controls included DM patients without CKD. Two variants in UBE3C, rs3802129[AA] and rs7807[CC], were found to be significantly associated with reduced kidney function in recessive model. In addition, the haplotype analysis revealed that the rs3802129/rs3815217 (Block 1) with A/G haplotype; the rs8101/rs7807 (Block 2) with T/C haplotype; had a higher risk of CKD phenotype when compared with their respective reference haplotype.
    In conclusion, we identified specific genetic variants in association with kidney-related traits among Taiwanese general population and hospital-based DKD patients. These eGFR-related variants or loci may contribute to kidney disease development, supported by previous functional studies. Further investigations are needed to confirm the findings in current Taiwanese-specific GWAS; as well as to establish the underlying mechanism of UBE3C variants contributing to the development of DKD.
    描述: 碩士
    指導教授：吳麥斯
    共同指導教授：張偉嶠
    委員：陳金順
    委員：張建國
    委員：王紋璋
    数据类型: thesis
    显示于类别:[臨床藥物基因體學暨蛋白質體學碩士學位學程] 博碩士論文

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