利用基因與環境因子進行台灣族群心血管疾病及痛風的SNP分析

Association of Single Nucleotide Polymorphisms with Hyperlipidemia and High-density lipoprotein in Taiwanese Based on Risk Factors

徐翠文(Tsui-Wen Hsu)

指導教授 ： 周明智

中山醫學大學/醫學院/醫學研究所/博士(2020年)

https://doi.org/10.6834/CSMU202000008

摘要

中文摘要
血管疾病 (cardiovascular disease；CVD) 疾病一直是全球重要公認的公共衛生議題，也是導致死亡主要原因之一。現今，精準醫療的發展，基因與環境因素是增加疾病易感性且日益討論的重要因子。近年來，全基因組關聯分析（genome-wide association study；GWAS ）研究證實，在不同種族中有許多與疾病相關的基因多型性 (Single nucleotide polymorphisms；SNP) 位點，且研究也已知不同基因型在不同族群中有獨特的影響。本研究使用台灣生物資料庫，納入正常人的基因多型性（genetic polymorphism），利用基因多型性之單一核苷酸多型性技術當作基因標記；偵測個人獨特基因表現及生理特性，導致個人罹患不同疾病的危險因子；例如：環境的暴露、飲食方式、生活習慣或帶有容易致病的基因的差異性；也可以幫助釐清致病因子 (環境、基因) 與疾病間的關係，因而進行基因與環境 (包括生活習慣、飲食方式、日常行為、職業….等）交互作用的相關研究。本研究利用台灣人體生物資料庫探討在台灣族群中人類白血球抗原 (human leukocyte antigen；HLA) 基因型rs2523608 GG and rs4713518 AA對於高血脂 (hyperlipidemia) 在痛風病人的影響。HLA-B是人類白細胞抗原的一個基因，座位於第六條染色體上與偵測痛風基因有關，且HLA-B*5801基因型在亞洲族群中已被證實與痛風有相關性。本研究第一階段利用台灣人體生物資料庫的資料，共有16878位年齡介於30至70歲的參與者納入研究，探討罹患高血酯在性別差異中是否會增加罹患痛風的風險？而高血酯對於痛風基因中rs2523608 GG 與rs4713518 AA的相關性？研究結果顯示，高血酯確實為痛風的危險因子；帶有rs2523608 GG型和rs4713518 AA型之基因型，在男女性別差異上，罹患高血酯都會增加罹患痛風相對危險性；尤其是女性，痛風合併高血酯，罹患風險高達7.454 (95% CI: 5.103–10.888)。
本研究第二階段透過台灣人體資料庫收集之基因與社會學變項資料，共有9075位參與者納入研究，利用性別差異及有無飲用咖啡探討罹患心血管疾病的風險。
肝脂酶 (hepatic lipase；LIPC) rs1800588及膽固醇脂轉運蛋白(cholesteryl ester transfer protein；CETP) rs1800775基因與膽固醇(cholesterol) 在心血管疾病中佔有重要的影響因子，可調節血液中膽固醇濃度的受體。在亞洲族群中，有許多研究都已經證實CETP rs1800775會影響血液中三酸甘油酯的濃度增加，導致高血酯症主要的原因。研究結果發現，性別與有無飲用咖啡及高密度脂蛋白膽固醇 (high-density lipoprotein cholesterol；HDL-C) 有交互作用；再將性別進行分層發現，女性在飲用咖啡與HDL-C有顯著相關性；調整干擾因子後，女性未停經者與停經者進行統計分析，女性在未停經者對於飲用咖啡與HDL-C有差異且未停經者飲用咖啡及HDL-C與LIPC rs1800588及CETP rs1800775基因有相關性；因此，在台灣女性族群未停經者飲用咖啡中能降低心血管疾病風險。
總體來說，本研究利用人體生物資料庫的資料，收集台灣組群在罹患痛風和心血管之間的相關變異分佈提供了額外的見解；研究結果顯示，rs 2523608 GG and rs 4713518 AA與痛風合併高血酯之間的顯著相關性，女性合併高血酯都有較高的機會得到痛風；另外，也建議LIPC rs1800588的基因型變異對於女性心血管疾病來說具有保護效果。許多研究指出慢性病的局部性或全身性發炎反應可能與痛風或心血管疾病有關，且彼此之間共病狀況十分常見。本研究結果可以做為未來更大型研究的參考並加以驗證。
本研究證實基因與生活型態所導致疾病的風險，在性別差異下與罹患高血酯的痛風病人及非基因因素(咖啡)對於心血管疾病的預防有相關性，所得數據和結論可以提供重要資訊。最終目標是維護健康及預防疾病，提供疾病預防及防治參考。
關鍵字：性別、痛風、高血酯、咖啡、高密度脂蛋白膽固醇、臺灣人體生物資料庫

關鍵字

性別 ； 痛風 ； 高血酯 ； 咖啡 ； 高密度脂蛋白膽固醇 ； 臺灣人體生物資料庫

並列摘要

Abstract
Gout and cardiovascular disease (CVDs) are health problems. Genetic and environmental factors are one of several factors thought to increase susceptibility to these diseases. Recent genome-wide association studies (GWAS) have recognized several loci associated with several disease conditions in different ethnic groups. Each genotype has a distinctive effect in different popultion. Genetic factors account for individual variability in ethnic groups that influence individual disease.This was realized using genotypic data in Taiwan Biobank including health people genetic information to determine markers whether specific polymorphic variants in HLA (Human Leukocyte Antigen) and LIPC（hepatic lipase）as well as CETP (cholesteryl ester transfer protein) genes are associated with susceptibility to Gout and CVDs in Taiwan. HLA gene is located on chromosome 6 and is associated with impaired gout disease. It is a Gout-associated gene particularly in European and Asian populations.
In the first phase of this study, genetic data from16878 participants (aged 30-70 years) in Taiwan Biobank were used to estimate the association between hyperlipidemia and sex amid carriers of rs2523608 GG and rs4713518 AA genotypes. Results showed that hyperlipidemic women with both genotypes (rs2523608 GG and rs4713518 AA) had relatively higher odds ratio than men. That uric acid was associated with a relatively higher odds ratio in men no matter the genotype. There was an interaction between hyperlipidemia and sex on gout risk among Taiwanese adults. Hyperlipidemia and sex were both associated with gout risk, with hyperlipidemia showing a greater impact.
The hepatic lipase (LIPC) and cholesterol ester transfer protein (CETP) are functional for protect against atherosclerosis and other CVDs. The variants rs1800588 (LIPC) and rs1800775 (CETP) have been respectively associated with higher and lower HDL-C levels. In the second phase of this study, complete genetic and sociodemographic data from 9075 participants in Taiwan Biobank were used to estimate the relationship between rs1800588 (LIPC) and rs1800775 (CETP) under stratification by sex and menopausal status. Among individuals with coffee drinking, Coffee consumption was significantly associated with higher HDL-C levels in only women (β = 0.81679; P = 0.0246). However, rs1800588 and rs1800775 variants were significantly associated with HDL-C in both sexes. the interaction between sex and coffee drinking on HDL-C was significant. After stratification by sex, coffee drinking was significantly associated with higher levels of HDL-C levels in women. Moreover, after stratification by menopausal status, coffee drinking was significantly associated with higher levels of HDL-C levels in non-menopausal women. We found that coffee drinking was significantly associated with higher HDL in women, after adjusting for confounders including rs1800588 (LIPC) and rs1800775 (CETP) variants in Taiwanese women.
Overall, these results have provided additional insights into the distribution of gout- and CVDs-associated variants in Taiwan. We continued to observe the hyperliperdemia had a high risk of gout in women and coffee consumption influence HDL-C protect against atherosclerosis and other CVDs. Our study provides evidence on the association between interaction between sex and hyperlipidemia on gout risk and coffee drinking and high-density lipoprotein cholesterol genetic and non-genetic factor.These results may serve as an incentive for larger scale studies.
Key words：sex; Gout; hyperlipidermia; coffee drinking; High-density
lipoprotein cholesterol (HDL- C); Taiwan Biobank

並列關鍵字

sex ； Gout ； hyperlipidermia ； coffee drinking ； High-density

參考文獻

References

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