- 學位論文
Fatty acid desaturase基因多型性與多元不飽和脂肪酸對第2型糖尿病患血液膽固醇濃度之影響
FADS gene variations interact with polyunsaturated fatty acids to affect cholesterol concentrations in type 2 diabetic patients
摘要
近年研究指出，FADS (fatty acid desaturase)基因多型性與心血管疾病具相關性，n-3多元不飽和脂肪酸(polyunsaturated fatty acid, PUFA)長久以來被認為可以降低心血管疾病風險，而FADS基因可轉錄脂肪酸去飽和酶，此為合成PUFA之rate-limiting enzymes。另外降血脂藥物與FADS基因多型性皆具有調控脂肪酸去飽和酶活性之作用。近來研究顯示，n-3 PUFA可能與FADS基因多型性產生交互作用進而調控血脂濃度，但是多位點基因多型性的人類研究並不多。 本研究探討，FADS SNP(single nucleotide polymorphism)、降血脂藥物與血漿血脂濃度以及脂肪酸去飽和酶活性之相關性，更進一步探討血漿PUFA濃度是否與FADS基因多型性產生交互作用，影響血脂濃度。 本研究橫斷面蒐集2008年糖尿病社區聯合照護網絡暨長期追縱研究計劃(DMIDS)之第2型糖尿病病患共874位，分析其FADS SNP rs174546、rs174547、rs174556、rs102275、rs174570、rs1535、rs174579、rs174589、rs174602、rs174620、rs2072114以及rs526126，檢視其頻率分布與HapMap CHD (Chinese in Metropolitan Denver, Colorado, USA)族群之頻率分佈相近。進一步，以有無使用降血脂藥物進行分層分析，並針對沒用降血脂藥物個案，依血漿 PUFA濃度高低進行分層分析 (n=192)。 在沒使用降血脂藥之個案發現FADS基因多型性與血脂濃度之相關性，在有使用降血脂藥物的病人則無發現此相關性。遂以沒用降血脂藥物192人，另外篩選出年齡、性別相符之有使用降血脂藥192人。分析結果，使用降血脂藥物病患有較高Δ6去飽和酶活性指標(C18:3n-6/C18:2n-6) (p=0.040)，Δ5去飽和酶活性指標(C20:4n-6/C20:3n-6)雖有增加之趨勢，但僅達邊緣顯著(p=0.059)。無論有無使用降血脂藥物，Δ6去飽和酶之活性指標在FADS rs174546、rs174547、rs174556、rs102275、rs174570、rs1535、rs174579、rs174589、rs174602以及rs2072114之基因多型性有顯著不同，而Δ5去飽和酶活性指標在FADS rs174546、rs174547、rs102275、rs174570、rs1535亦有顯著之差異。進一步探討FADS 基因多型性與降血脂藥物之交互作用，未觀察到相關性。第二部分研究以沒用降血脂藥物192人，以50百分位數將ALA/LA、n-3/n-6 PUFA以及n-3 LCPUFA分為高低兩組，探討血漿PUFA濃度與FADS基因多型性是否調控血脂濃度。在HDL濃度部分，僅在低ALA/LA、低n-3/n-6 PUFA及低n-3 LCPUFA，HDL濃度在rs174547、rs174556、rs102275、rs174570、rs1535、rs174602以及rs2072114基因型間有顯著差異。在LDL濃度部分，僅在血漿低ALA/LA指標，LDL濃度在rs174546、rs174556、rs102275、rs174570、rs174602、rs2072114之不同基因型有顯著差異。然而，在高ALA/LA、n-3/n-6 PUFA及n-3 LCPUFA攝取狀態，各FADS SNPs與HDL及LDL濃度均無明顯差異。 結論，僅在沒有降血脂藥物的情況下，FADS基因多型性與血漿膽固醇濃度具相關性。降血脂藥物可顯著提升Δ6去飽和酶活性，而某些FADS基因多型性亦與Δ5及Δ6去飽和酶活性相關，但降血脂藥物與FADS基因多型性並無顯著交互作用。在血漿n-3 PUFA分層分析，體內血漿n-3 PUFA濃度較低者，其血漿HDL與LDL濃度可能受到FADS基因多型性影響。
並列摘要
Previous literatures have shown taht fatty acid desaturase (FADS) gene polymorphisms are associated with risk of cardiovascular disease (CVD). n-3 polyunsaturated fatty acids (PUFA) have been implicated to have beneficial effects on the reducing risks of CVD. FADS gene encodes rate-limiting enzymes which are required for PUFA synthesis. Evidence indicates lipid-lowering drugs and FADS genetic variations can affect fatty acid compositions by modifying desaturase activities. Additionally, n-3 PUFAs may also interact with FADS SNPs to affect lipid concentrations. Up to date, there have been very limited human studies availble. This study aimed to investigate the independent and combined effects of lipid-lowering drugs and FADS SNPs on the fatty acid desaturase activities. Further, we aimed to explore whether plasma n-3 PUFA status interacts with FADS SNPs to affect plasma lipid concentrations. A total of 874 type 2 diabetic patients were cross-sectionally recruited from the Diabetes Management through Integrated Delivery System (DMIDS) cohort. FADS SNPs (rs174546, rs174547, rs174556, rs102275, rs174570, rs1535, rs174579, rs174589, rs174602, rs174620, rs2072114, and rs526126) were genotypped and compared the frequencies to the HapMap database. The genotype frequencies were comparable to the CHD (Chinese in Metropolitan Denver, Colorado, USA) population. The association between FADS variations and blood lipid concentrations were only found in those without use of lipid-lowering drug. There were total of 192 patients without use of lipid-lowering drug and age and sex-matched 192 patients with use of lipid-lowering drug were selected. Lipid-lowering drug use correlated with significantly higher Δ6 desaturase activities, but increases in Δ5 desaturase activities only reached a marginal significance (p=0.059). Stratified by lipid-lowering drug use,Δ6 desaturase activities among FADS polymorphisms (rs174546, rs174547, rs174556, rs102275, rs174570, rs1535, rs174579, rs174589, rs174602, and rs2072114) genotypes were significantly different in user as well as in non-user.Δ5 desaturase activities were only different in rs174546, rs174547, rs174556, rs102275, rs174570, and rs1535 genotypes in user as well as in non-user. However, there was no significant interaction between lipid-lowering drug use and FADS SNPs. In low ALA/LA, n-3/n-6 PUFA, and n-3 LCPUFA status, HDL concentrations were significantly different among FADS SNP genotypes (rs174547, rs174556, rs102275, rs174570, rs1535, rs174602, and rs2072114). In terms of LDL, only low ALA/LA status, LDL concentrations were significantly different among genotypes of SNP rs174546, rs174556, rs102275, rs174570, rs174602, and rs2072114. However, in the group of high ALA/LA, n-3/n-6 PUFA, and n-3 LCPUFA status in plasma, HDL and LDL concentrations did not differ. In conclusion, HDL and LDL concentrations may be modified by FADS genetic variations only in those without use of lipid-lowering drug. Lipid-lowering drug significantly associated with elevated Δ6 desaturase activities. Δ5/Δ6 desaturase activities may also be modified by some FADS SNPs. In patients with low n-3 PUFA status, HDL and LDL concentrations were associated with FADS SNP genotypes.