腫瘤壞死因子的單一核苷酸多型性與血漿砷之交互作用對腎絲球過濾率之影響

Inter-relationship of Tumor Necrosis Factor (TNF) Single nucleotide polymorphism (SNP) and plasma-arsenic to estimated glomerular filtration rate (eGFR)

林冠菻(Kuan-Lin Lin)

指導教授 ： 莊弘毅

高雄醫學大學/健康科學院/公共衛生學系公共衛生學碩士班/碩士(2019年)

摘要

前言:
毒物進入人體後將引起體內腫瘤壞死因子(TNF-α)升高，藉由氧化壓力及發炎反應對人體(如:血管內皮細胞等)造成損害；砷為IARC Class 1致癌物，研究已指出砷會使人體產生多種病症如皮膚角化、周邊神經病變、周邊血管病變與多種癌症，且諸多研究皆顯示砷暴露與腎絲球過濾率(eGFR)呈現負相關或與蛋白尿盛行率有關。
目的:
目前很少研究有提到砷暴露與TNF-α單一核酸多型性對eGFR的影響，故本研究欲深入探討三者之間的關係。
方法:
由臺灣人體生物資料庫(Taiwan Biobank, TWB)抽樣選出之500位三十至七十歲成年一般社區民眾。運用其基因晶片篩選出TNF-α基因中的7個SNP位點，合併問卷、生化檢測等資料，與購自TWB之此研究族群血漿(以高雄醫學大學環境醫學研究中心的電感耦合電漿質譜儀(ICP-MS)分析血漿砷(Arsenic))；調整BMI、高血壓、高血脂、腎結石、抽菸習慣後，以描述性與複回歸統計探討SNP、估算腎絲球過濾率(eGFR)、血漿砷三者之間的關聯。
結果:
即使在一般社區民眾(非職業暴露族群)中，砷暴露依然對eGFR的下降造成顯著的影響(β=-6.47~9.01, p<0.0001)。rs1800629本身即帶有調控TNF-α的性質，其與血漿砷是有交互作用的；AG型者比GG型者的eGFR顯著降低了9.59 ml/min/1.73m2 (p<0.05)，且參照Dominant model可推論A allele為risk allele。rs769177與血漿砷並無交互作用，其中為TT或TC型者會比CC型者的eGFR顯著高出4.02 ml/min/1.73m2 (p<0.05)。rs769176與血漿砷有交互作用，若某人為TC型，血漿砷濃度越高eGFR也就越高；假設令其血漿砷由lnQ3降至lnQ1，則eGFR反而會下降9.45 ml/min/1.73m2。
結論:
現今普遍認為過多TNF-α是造成細胞破壞的因素，而本研究發現TNF-α基因中某些SNP位點對砷暴露破壞eGFR卻具有保護作用；這些位點對TNF-α的調控機制、是否面對其他環境暴露造成的發炎反應也具有相同的效果，尚需進一步研究證實。

關鍵字

腫瘤壞死因子 ； 單一核苷酸多型性 ； 血漿砷 ； 腎絲球過濾率

並列摘要

Background:
When poisons enter human body, tumor necrosis factor (TNF-α) will rise and cause damage to tissues (such as vascular endothelial cells) through oxidative stress or inflammatory reaction. Arsenic is IARC Group 1A carcinogens, and previous researches have pointed out that arsenic will bring us many health problems, such as skin keratosis, peripheral neuropathy, peripheral vascular disease and many kinds of cancers. Also, some studies have shown that arsenic exposure is negatively correlated with estimated glomerular filtration rate (eGFR), or with prevalence of proteinuria.
Objective:
At present, there are few studies focus on the effects of arsenic exposure and TNF-αsingle nucleotide polymorphism(SNP) to eGFR, so this study is intended to explore the inter-relationship between the three.
Materials and methods:
A sample of 500 adults aged 30 to 70 years old, selected from Taiwan Biobank (TWB). Using the gene chip to screen out 7 SNPs of TNF-α gene, combined with questionnaires, biochemical tests and other data, and the plasma of the study group purchased from TWB(analysis of arsenic in plasma by the inductively coupled plasma mass spectrometer (ICP-MS) of the Environmental Medicine Research Center of Kaohsiung Medical University). After adjustment of BMI, hypertension, hyperlipidemia, kidney stones, and smoking habits, then using descriptive and complex regression statistics to explore the association between SNPs, eGFR, and plasma arsenic.
Results:
Even in the general community (non-occupational exposure groups), arsenic exposure still had a significant effect on the decline of eGFR (β=-6.47~9.01, p<0.0001). rs1800629 itself has the property of regulating TNF-α, which interacts with plasma arsenic; AG type has a significantly lower eGFR than GG type by 9.59 ml/min/1.73 m2 (p<0.05), and reference to dominant model can infer that A allele is risk allele. rs769177 had no interaction with plasma arsenic, and those with TT or TC type were significantly higher than the eGFR of CC type by 4.02 ml/min/1.73 m2 (p<0.05). rs769176 interacts with plasma arsenic. If a person is TC type, the higher the plasma arsenic concentration is, the higher the eGFR is. If the plasma arsenic is reduced from lnQ3 to lnQ1, the eGFR will decrease by 9.45 ml/min/1.73 m2.
Conclusion:
It is generally believed that TNF-α is a factor causing cell destruction, but this study found that certain SNP of TNF-α gene have protective effects on the decrease of eGFR caused by arsenic exposure. Still we need further research to confirm whether the protective regulation mechanism of these SNPs also work on other environmental exposures.

並列關鍵字

Tumor Necrosis Factor ； TNF ； Single nucleotide polymorphism ； SNP ； plasma-arsenic ； estimated glomerular filtration rate ； eGFR

參考文獻

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