台灣蘭陽盆地砷暴露地區NQO1、NFKB3基因多形性與心血管疾病之相關性研究

心血管疾病是全世界的主要死因之一，占死亡總數的31%。無機砷是地殼中常見的自然元素，能夠經由飲用水系統進入到人體，於代謝的過程中產生反應性氧化物種 (reactive oxygen species；ROS)，造成體內氧化壓力上升並且活化發炎反應，最終導致心血管疾病的發生，而NQO1、NFKB3分別與氧化壓力、發炎反應的調控有關，因此，我們執行病例對照研究以探討NQO1與NFKB3基因多形性對於心血管疾病的相關性。研究樣本取自東北蘭陽盆地砷暴露地區的居民，經由受過標準化訓練的訪員進行面訪，透過結構式問卷收集相關資料，包括了基本人口學特性、生活習慣、疾病史，並且進行唾液檢體的採集。個人家戶的井水量測則是以氫化物原子吸收光譜法量測。問卷中自答有心臟病、心肌梗塞或是中風者作為病例組，根據性別與年齡進行1：2的頻率配對後，總共納入405名心血管疾病病例與810名對照組。藉由聚合酶鏈鎖反應 (polymerase chain reaction；PCR) 與限制片段長度多形性 (restriction fragment length polymorphism；RFLP) 鑑定NQO1 rs10517、rs1800566以及NFKB3 rs2306365之基因型。研究結果發現，調整性別、年齡、抽菸、酒精攝取、高血壓、糖尿病等危險因子後，相較於飲水砷濃度<10 μg/L，飲水砷濃度>50 μg/L的心血管疾病風險增加35% (95% CI = 1.00-1.83)；累積砷暴露1000-4999.99 µg/L × 年者有較高罹患心血管疾病的風險，為累積砷暴露<1000 µg/L × 年的1.31倍 (95% CI = 0.99-1.72)。在危險因子分層之下探討NQO1、NFKB3基因多形性與心血管疾病的風險，於男性、有抽菸習慣與飲水砷濃度10-50 μg/L的分層之中，皆發現攜帶TT基因型者相較於C對偶基因，分別有1.77倍 (95% CI = 1.04-3.03)、2.01倍 (95% CI = 1.09-3.73)以及1.80倍 (95% CI = 0.95-3.43) 的心血管疾病風險；且約有50%的心血管疾病風險是來自NQO1 rs10517 TT基因多形性分別與性別、抽菸習慣與飲水砷暴露對於心血管疾病的交互作用影響。以NQO1 rs10517、rs1800566危險基因型合併來探討與心血管疾病風險之相關性，結果發現在飲水砷濃度10-50 μg/L的分層之中，帶有危險基因型者增加45% (95% CI = 0.93-2.25) 的心血管疾病風險；其中危險基因型與飲水砷暴露10-50 μg/L對於心血管疾病風險的交互作用占42%的危險性。最後將NQO1 rs10517、rs1800566與NFKB3 rs2306365危險基因型合併後，在飲水砷濃度介於10-50 μg/L的分層之中發現，相較於一個以下的危險基因型者，攜帶兩個以上危險基因型者有1.64倍 (95% CI = 1.03-2.63) 的心血管疾病風險，且發現NQO1 rs10517、rs1800566與NFKB3 rs2306365危險基因型個數 (≧2) 與飲水砷暴露10-50 μg/L對於心血管疾病風險具有顯著相加性交互作用 (RERI = 0.84；95% CI = 0.03-1.66)，其心血管疾病的風險有49%是來自於交互作用所產生的影響。砷暴露與心血管疾病風險增加有關，NQO1 rs10517、rs1800566與NFKB3 rs2306365危險基因型個數 (≧2) 與飲水砷暴露10-50 μg/L對於心血管疾病風險具有顯著相加性交互作用，中度砷暴露 (10-50 μg/L) 的族群當中，帶有較多的NQO1 rs10517、rs1800566與NFKB3 rs2306365合併之危險基因型個數可能與罹患心血管疾病有關。

關鍵字

砷暴露； NAD (P) H:quinone oxidoreductase 1 (NQO1) ； Nuclear factor kappa B subunit 3 (NFKB3) ；心血管疾病

並列摘要

Backgroung: Cardiovascular disease (CVD) is one of the major causes of death in the world, accounting for 31% of deaths. Inorganic arsenic is a natural element of the earth's crust, which can enter human body through drinking water. Reactive oxygen species (ROS) are generated from metabolism of inorganic arsenic, resulting in increased oxidative stress and inflammation. Eventually, it leads to the development of CVD. NAD (P) H:quinone oxidoreductase 1 (NQO1) and Nuclear factor kappa B subunit 3 (NFKB3) have been reported to mediate oxidative stress and inflammatory response. Therefore, we conducted a case-control study to investigate the association between genetic polymorphisms of NQO1, NFKB3 and the risk of CVD. Method: The study subjects were recruited from the arseniasis-endemic area in Lanyang Basin of northeast Taiwan. Well-trained interviewers performed the standardized personal interview using a structured questionnaire for the study subjects and collected their saliva samples. Hydride generation combined with flame atomic absorption spectrometry was used to determine the arsenic concentration from drinking water. A total of 405 study subjects with self-report CVD history from questionnaire were defined as CVD cases. A total of 810 controls were frequency matched with cases by gender and age (±5 years) in a ratio of 1:2. We used polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to determine the genotypes of selected SNPs from NQO1 (rs10517, rs1800566) and NFKB3 (rs2306365). Result: After adjusting gender, age, smoking, alcohol drinking, hypertension and diabetes, subjects with arsenic exposure >50 µg/L significantly increased 35% risk of CVD (OR = 1.35, 95%CI = 1.00-1.83) as compared to those with arsenic exposure <10 µg/L. In study subjects with cumulative arsenic exposure 1000-4999.99 µg/L × years, the risk of CVD increased to 1.31 folds (95%CI = 0.99-1.72) as compared to cumulative arsenic exposure <1000 µg/L × years. In study subjects with arsenic exposure 10-50 µg/L, who were males and smokers, an increased odds for CVD were observed in NQO1 rs10517 TT carriers. About 50% risk is derived from interactions between gender, smoking, arsenic exposure and NQO1 rs10517 TT genotype on the risk of CVD. We evaluated the combined effect of NQO1 rs10517 and rs1800566 risk genotype on risk of CVD. In study subjects with arsenic exposure 10-50 µg/L, an increased odds (OR = 1.45, 95%CI = 0.93-2.25) for CVD were observed in NQO1 combined risk genotype carriers. About 42% risk is derived from interaction between NQO1 combined risk genotype and arsenic exposure on the risk of CVD. Finally, we evaluated the combined effect of NQO1 rs10517, rs1800566 and NFKB3 rs2306365 risk genotype on the risk of CVD. In study subjects with arsenic exposure 10-50 µg/L, carriers with more than two risk genotypes significantly increased the risk of CVD (OR = 1.64, 95%CI = 1.03-2.63) as compared to those carrying one or nil risk genotype. The combination of NQO1 rs10517, rs1800566 and NFKB3 rs2306365 risk genotype with arsenic exposure has a positive additive interaction (RERI = 0.84; 95% CI = 0.03-1.66) on the risk of CVD. In addition, Forty nine percentage of CVD risk was due to the effects of interaction. Conclusions: Arsenic exposure was associated with an increased risk of CVD. NQO1 rs10517, rs1800566 and NFKB3 rs2306365 risk genotypes equal or greater than two and arsenic exposure 10-50 µg/L had a significant interaction on the risk of CVD. In study subjects with moderate arsenic exposure (10-50 µg/L), more risk genotypes of NQO1 rs10517, rs1800566 and NFKB3 rs2306365 might be associated with the risk of CVD.

並列關鍵字

Arsenic exposure ； NAD (P) H:quinone oxidoreductase 1 (NQO1) ； Nuclear factor kappa B subunit 3 (NFKB3) ； Cardiovascular disease (CVD)

參考文獻

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台灣蘭陽盆地砷暴露地區NQO1、NFKB3基因多形性與心血管疾病之相關性研究

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