- 學位論文
FADS基因多型性與第二型糖尿病人血脂狀態之相關性
The relationships between FADS polymorphisms and blood lipid status in type 2 diabetic patients
摘要
心血管疾病為導致糖尿病死亡率之重要併發症，n-3多元不飽和脂肪酸(polyunsaturated fatty acids, PUFAs)長久以來被認為對心血管疾病患者是有益的。Fatty acid desaturase (FADS)基因可轉錄脂肪酸去飽和酶，此為合成PUFA之rate-limiting enzymes，而FADS基因多型性被發現與血脂濃度及脂肪酸去飽和酶活性相關，但是FADS基因多型性與血脂及脂肪酸去飽和酶活性相關性之研究大部分在健康族群進行探討。本研究目地探討第2型糖尿病患者之FADS基因多型性與血脂濃度之相關性，更進一步探討與血漿中脂肪酸去飽和酶活性之關係。 本研究對象來自糖尿病社區聯合照護網絡暨長期追縱研究計劃(Diabetes Management through Integrated Delivery System, DMIDS)，2008年橫斷面收案第2型糖尿病患共874位，收集基本資料及臨床生化值，挑選9個FADS1/2基因多型性 (FADS1: rs174537、rs174548、rs174550; FADS2: rs174553、rs174575、rs174576、rs174583、rs498793、rs2727270) 進行genotyping。本研究挑選其中173位患者沒有使用statin 以及fibrate 類的降血脂藥，分析FADS1/2基因多型性與血脂濃度之相關性，再進一步探討FADS基因多型性與血漿中脂肪酸去飽和酶活性之關係。利用ANOVA及independent t-test analysis分析比較血脂濃度與去飽和酶活性在不同基因型間的差異。 此研究分析之FADS 1: rs174548及FADS2 : rs174576、rs174583、rs498793頻率分布與HapMap CHD (Chinese in Metropolitan Denver, Colorado, USA) 族群相近，但因HapMap為健康對照組，故未來需要擴大疾病組樣本數及募集健康對照組，才能正確比較基因頻率與文獻之異同。FADS2 SNP rs174576可作為一個tag SNP代表FADS1 : rs174548、rs174550及FADS2 : rs174583、rs2727270，在此LD block內的SNPs皆呈高度相關 (r2≥0.8)。探討FADS基因多型性與臨床生化值相關之結果顯示，tag SNP rs174576之C allele攜帶者其血漿HDL-C濃度顯著較高之趨勢，但與total cholesterol、triglyceride、non-HDL-C、LDL-C濃度無關。進一步探討與脂肪酸去飽和酶活性發現，tag SNP rs174576之C allele攜帶者有較高的脂肪酸去飽和酶活性，包括Δ5 (20:4n-6/20:3n-6) 與Δ6 (18:3n-6/18:2n-6)去飽和酶活性、n-3 (20:5 n-3/18:3 n-3) 與n-6 (20:4 n-6/18:2 n-6) pathway活性。其它與tag SNP呈現高度相關的SNPs (FADS1: rs174548 C allele、rs174550 T allele及FADS2 : rs174583 C allele、rs2727270 C allele)亦呈現類似結果，顯示此LD block與血漿膽固醇濃度(HDL-C) 和脂肪酸去飽和酶活性有關。
並列摘要
Cardiovascular disease (CVD) is considered one of the leading causes of death of type 2 diabetes. N-3 polyunsaturated fatty acids (PUFAs) have been shown to have beneficial effects on the risks of CVD. Fatty acid desaturase (FADS) gene encodes rate-limiting enzymes for PUFA synthesis, and its genetic variations have been shown to correlate with blood lipids concentrations and desaturase activities. Up to date, studies reporting these associations were mostly conducted in healthy populations. The aim of this study was to explore whether the FADS single nucleotide polymorphisms (SNPs) correlate with blood lipid concentrations and fatty acid desaturase activities in type 2 diabetes. A total of 874 type 2 diabetic patients were cross-sectionally recruited from the Diabetes Management through Integrated Delivery System (DMIDS) cohort at 2008. We collected demographic information and analyzed clinical biomarkers. Nine FADS1/2 SNPs (FADS1: rs174537, rs174548, rs174550; FADS2: rs174575, rs174576, rs174583, rs498793 and rs2727270) were genotyped. Of which, 173 patients without using lowering lipid drugs (statin and fibrate) and with complete plasma fatty acid measures were selected into further analyses. ANOVA-based models and independent t-test analysis were applied to compare the differences of lipid concentrations and desaturase activities among FADS genotypes. In our diabetic subjects, frequencies of FADS1 SNP rs174548 and FADS2 SNPs rs174576, rs174583 and rs498793 genotypes were comparable to those reported of the HapMap CHD (Chinese in Metropolitan Denver, Colorado, USA) population. The HapMap dataset provides human genome information only based on healthy population. Future investigation is needed to increase sample size in DM groups as well as to recruit a group of healthy control in order to examine and further compare the frequencies of FADS SNP with those documented in the literature. Further, we found that FADS2 SNP rs174576 can be the tag SNP of rs174548, rs174550, rs174583 and rs2727270. These SNPs were in strong linkage disequilibrium (LD) (r2≥0.8). Our results showed that tag SNP rs174576 C allele was associated with higher concentrations of HDL-C, while was not associated with total cholesterol、triglyceride、non-HDL-C、LDL-C concentrations. In addition, rs174576 C allele carriers had higher levels of fatty acid desaturase activities, including Δ5 (20:4n-6/20:3n-6) and Δ6 (18:3n-6/18:2n-6) desaturase activities and n-3 (20:5 n-3/18:3 n-3) and n-6 (20:4 n-6/18:2 n-6) pathway activities. Other SNPs (rs174548, rs174550, rs174583 and rs2727270) in the same LD block also showed similar results, indicating that this LD block was associated with plasma cholesterol concentrations (HDL-C) and desaturase activities. In conclusion, tag SNP rs174576 C allele was associated with higher concentrations of HDL-C. Further, tag SNP rs174576 as well as highly-correlated SNP including rs174548、rs174550、rs174583 and rs2727270 also appeared to associate withΔ5/Δ6 desaturase and n-3/n-6 pathway activities. Whether the genetic variation and their subsequent modeification in blood lipids as well as desaturase activities would exert effects on diabetic complications development such as risks of cardiovascular diseases warrant further study.
參考文獻
延伸閱讀
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