以孟德爾隨機化探究血小板與高血壓之因果關係

Using Mendelian randomization method to elucidate the causal relationship between platelet and hypertension

吳孟駿(Meng-Chun Wu)

指導教授 ： 盧子彬

國立臺灣大學/公共衛生學院/流行病學與預防醫學研究所/碩士(2019年)

https://doi.org/10.6342/NTU201902915

摘要

中文摘要
背景
從臨床上及生物機制角度上，血小板都在增加血栓形成的傾向中扮演關鍵的角色，並且已被證實和心血管疾病有關。過去的研究指出，血小板和高血壓有相關，然而這些研究可能受到干擾偏差或是研究設計上的限制無法達成因果推論。另外，過往也缺乏在血小板指標中重要的血小板數量與高血壓的相關性研究。我們採用和血小板數量相關的單核苷酸多態性為工具變項，執行遺傳風險評分孟德爾隨機化，藉此推論血小板數量和高血壓的因果關係。

材料及方法
在我們的研究中，我們隨機從台灣人體生物資料庫抽取15,996位年齡介於30歲到70歲的台灣漢民族作為我們的研究對象。暴露因子及臨床結果分別為第一次量測的血小板數量及經定義的高血壓。包含有646,735單核苷酸多態性在內的基因資料，所有分析的資料皆取自相同的來源。我們設定4個不同的情境取得適合的單核苷酸多態性並降低干擾因子的干擾。我們利用計算遺傳風險評分及以權重中位數模型建立的遺傳風險評分孟德爾隨機化來推論血小板和高血壓間的因果關係。

結果
在相關性分析的部份，我們分別在只有納入性別和年齡當作共變項的羅吉斯回歸以及所有變數納入作為共變項的羅吉斯回歸都得到血小板數量和高血壓有正向且顯著的相關性(p值分別為3.8e-10和2.85e-3)。納入大於2個基因變異作為工具變項的所有情境中，遺傳風險評分孟德爾隨機化亦得到一致正向且顯著(p值< 0.05)的結果。

結論
我們有足夠的統計證據說明血小板數量和高血壓的因果關係。在未來，血小板可以做為高血壓的一項危險因子以作為臨床以及預防性治療開發的相關應用。

關鍵字：孟德爾隨機化，遺傳風險評分，血小板數量，高血壓，台灣人體生物資料庫，因果推論

關鍵字

孟德爾隨機化 ； 遺傳風險評分 ； 血小板數量 ； 高血壓 ； 台灣人體生物資料庫 ； 因果推論

並列摘要

ABSTARCT
BACKGROUND
Platelet has a crucial role in the increasing thrombotic tendency from both clinical and biological perspectives, and has already been reported correlated to cardiovascular diseases. Some of the previous studies showed that platelet has correlation to hypertension as well, however, with some confounding bias or design restrictions so that the causal inference didn’t succeed. Also, there would be absence in the form of platelet count, which is one of the important platelet indices, in the previous studies. We have utilized several single nucleotide polymorphisms (SNPs) related to platelet count as instrumental variables to perform genetic risk score Mendelian randomization to make the causal inference of platelet count on hypertension.

MATERIAL AND METHODS
There were 15,996 healthy Taiwanese Han individuals aging from years 30 to 70 randomly picked up from the Taiwan Biobank project in our study. The baseline of platelet count and hypertension were used as an exposure and an outcome, and the clinical data and genomic data with 646,735 SNPs were all coming from the same dataset. We set 4 different scenarios to choose the appropriate SNPs and eliminated the interventions from confounding factors. The genetic risk score development and the further genetic risk score Mendelian randomization in weighted-median model was then executed to elucidate the causal relationship of platelet count on hypertension.

RESULTS
There was significantly positive relationship of platelet count on hypertension with only age and sex (p-value = 3.80 e-10) and all the confounding included in logistic regression analysis (p-value = 2.85 e-3). The positive causal relationships between platelet count and hypertension were also consistently statistically significant (p-value < 0.05) in 3 different scenarios with more than 2 SNPs as instrumental variables in genetic risk score Mendelian randomization.

CONCLUSION
Our study had enough evidence to state that platelet count had causal relationship on hypertension. Platelet count could be taken as the risk factor of the hypertension, and then related clinical applications and preventive therapeutic treatments could be considered in the near future.

並列關鍵字

Mendelian randomization ； genetic risk score ； platelet count ； hypertension ； Taiwan Biobank ； causal relationship

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