- 學位論文
鉛暴露和PON1酵素及基因型與血脂肪之追蹤研究
A Longitudinal Study of Blood Lead,PON1 Enzyme and Genotypes, and Lipid Profiles
摘要
背景與目的： 職業性鉛暴露對心血管的危害，包括促使動脈粥樣硬化的形成。在HDL上的PON1蛋白，防止LDL被氧化且對動脈粥樣硬化具保護作用。PON1基因多型性中具功能性SNPS的分佈位點,兩個座落於編碼區Q192R、L55M；一個座落於啟動子區C(-108)T，對心血管疾病的易感性已被廣泛研究。本研究以三年追蹤鉛暴露勞工之血鉛、血清PON1活性及基因多型性與血脂的相關探討。 方法： 某鉛作業勞工141人，三年前後追蹤資料取自2002到2005年，透過員工健康檢查收集樣本與問卷。實驗室分析方法，Q192R、L55M、C(-108)T之基因型檢測，利用PCR-RFLP方法；PON1對於三種不同受質活性(AREase、POase、DZOase)測量，採用microfiter plate reader(SpectraMax,Molecular Devices) 方法。前後重複測量採用廣義估計方程式(GEEs)進行多變項分析，經HDL調整後之PON1活性作為依變項進行研究分析。 結果： GEE模式分析結果：(一)如果受試者的HDL是40 mg/dL，則血鉛每增加1μg/dL，其AREase活性下降3.68 μmol/min/mL；POase活性下降3.04 μmol/min/mL；DZOase活性下降28.8 μmol/min/mL，且達顯著差異；(二)血鉛檢測差值(δ_pbb)預測經HDL調整後之PON1活性，血鉛增加組 (δ_pbb>3)皆降低酵素活性，但未達顯著差異；(三) Q192R基因型預測經HDL調整後之PON1活性，RR基因攜帶者顯著影響POase/HDL，QR、QQ對偶基因顯著影AREase/HDL、DZOase/HDL活性；(四) Q192R與血鉛之交互作用預測經HDL調整後之POase/HDL，未達顯著差異但發現RR基因攜帶者對鉛毒性具易感性。 結論： 追蹤三年的鉛作業勞工，RR基因攜帶者對鉛的毒性易感性較高，如果其HDL為40 mg/dL，則血鉛每增加10 ug/dL，則POase酵素活性將顯著下降至30.4 μmol/min/mL，罹患心血管疾病約增加15.2~22.8％的風險。
並列摘要
Background: Occupational lead exposure was well known to associate with risk of cardiovascular disease via the pathway of atherosclerosis formation. PON1 protein which located at HDL, might reduce the formation of atherosclerosis by reducing LDL oxidized. Three specific single nucleotide polymorphism (SNP), Q192R, L55M ,and C(-108)T), in PON1 polymorphism were broadly studied in the past. Hence, this longitudinal study aimed at investigating the relationship among blood lead level, PON1 polymorphism and serum lipid in workers with occupational lead exposure. Methods: Subjects included 141 lead workers whose blood samples and questionnaire were performed in the annual health examination survey, conducted from year 2002 to 2005. Q192R, L55M and C(-108)T were examined with PCR-RFLP. The activity of PON1, which recognized as AREase, POase and DZOase, were measured by microfiter plate reader(SpectraMax, Molecular Devices). The activity of PON1 adjusted with HDL was defined as dependent variable, and repeat measurements were analyzed with GEE method. Results: If the subject had a 40 mg/dL of HDL, the increment of 1μg/dL of blood lead level, the activity of AREase, POase ,and DZOase were significantly decrease to 3.68, 3.04 ,and 28.8 μmol/min/mL respectively by GEE analysis. For the assessment of the longitudinal values of blood lead levels, the group with blood lead increment (δ_pbb>3) declined the PON1 activity but insignificantly. The subjects with RR type (Q192R) affected POase significantly; however, the subjects with QR, QQ types significantly affected AREase and DZOase activity respectively. For the assessment of the interaction between Q192R and blood lead level to the POase, we found that subjects with RR allele were susceptible to lead toxicity. Conclusion: This 3 years longitudinal study demonstrated that lead workers with RR type of Q192R were susceptible to lead toxicity. For 10 ug/dL increment of blood lead level, the enzyme activity of POase significantly declined 30.4 μmol/min/mL in a person with 40 mg/dL of HDL and raised the risk of cardiovascular disease by 15.2~22.8％.