高血脂病人其基因多型性與基礎生化值及史達汀效果之影響

Abstract

高血脂病人血中膽固醇及三酸甘油脂 (triglyceride，TG) 過高，易造成動脈硬化、血栓及中風。目前臨床上最廣為使用的降血脂藥─史達汀 (statin) 類藥物，其能抑制HMG-CoA還原酶 (3-hydroxy-3-methylglutaryl-coenzyme A reductase)，進而減少內生性膽固醇合成與增加細胞膜上的低密度膽固醇受體，導致血中總膽固醇 (total cholesterol，TC)、低密度膽固醇 (low-density lipoprotein cholesterol，LDL-c)及三酸甘油脂濃度減少，並使高密度膽固醇 (high-density lipoprotein cholesterol，HDL-c) 濃度增加。但史達汀治療效果仍存在廣大的變異性，而基因多型性可能可解釋部分原因。 本研究共納入209位高血脂病人，使用atorvastatin (ATV) 或 rosuvastatin (RSV) 四週以上，且有治療前後血脂檢驗值供分析，再收集受試者的DNA進行基因型檢定，篩選與血脂生成、運送或代謝有關的基因，例如ABCA1、ABCG5/G8、APOA5、CETP、FDFT1、LDLR等；與史達汀代謝運送有關的基因，如ABCB1、ABCG2、CYP2C9/19、CYP3A5、SLCO1B1等，共24個SNPs，並分析基因多型性對於基礎生化值或ATV及RSV治療效果是否有相關性。另一方面，欲研究目前最強的史達汀類藥物 ─ RSV的降脂效果與安全性，擴大篩選ABCA1、APOA1、APOA5、CETP、LIPC、LPL、PPARA/D/G等48個SNPs，再進一步探討SNPs或單套型與受試者在RSV治療後TC、TG、LDL-c、HDL-c改變百分比、TG/HDL和TC/HDL比值改變量之間的相關性。 在基礎生化值方面，本研究發現7個相關的SNPs，分別為ABCG2 (rs2231142)、APOA5 (rs3135506)、CETP (rs708272、rs17245715、rs12597250)、LDLR (rs5929)、MIA3 (rs17465637)；在與史達汀降血脂效果相關的SNPs方面，本研究找到2個SNPs與ATV降脂效果有相關性，分別是LDLR (rs5925) 與LDLR (rs4508523)。在RSV方面，有4個SNPs與降血脂效果有顯著影響，分別是ABCG2 (rs2231142)、misc (rs501120)、PPARA (rs1800234)、PPARG (rs4684847)。在單套型分析中，本研究發現ABCA1之單套型，受試者若為較不常見的單套型 C-T-G-G-G-A (頻率：7.899%)，其基礎生化值中的總膽固醇與LDL-c濃度比較為常見的兩個單套型 C-T-G-G-G-G (頻率：13.177%)、T-T-G-G-G-A (頻率：12.033%) 高。在給予RSV治療後，TG濃度改變百分比在最不常見的單套型C-T-G-G-G-A中不降反而些微上升 (C-T-G-G-G-G：T-T-G-G-G-A：C-T-G-G-G-A，-23.904±24.623%：-20.192±24.596%：0.4781±37.064%，p value= 0.019)，且在TG/HDL比值改變量中下降最少 (C-T-G-G-G-G：T-T-G-G-G-A：C-T-G-G-G-A，-1.015±1.7793：-0.8910±1.3887：-0.2638±1.4789，p value= 0.016)。 本研究發現某些基因型與受試者的基礎生化值相關，顯示先天遺傳在血脂濃度方面有其重要性，且基因多型性可能影響ATV與RSV的降脂效果，故本研究可提供高血脂病人在心血管疾病危險性之預防與治療上作為參考。結果是否可於更大的台灣人族群中得到驗證，需未來更多進一步之研究。

Elevated blood cholesterol and triglycerides (TGs) are so-called hyperlipidemia and implicated in the development of atherosclerosis with risks for thrombosis, heart attack and stroke. Currently statins become the most widely used lipid-lowering drugs. Statins inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, a rate-limiting enzyme of cholesterol biosynthesis pathway, resulting in the reduction of endogenous cholesterol synthesis and the increase of low-density lipoprotein (LDL) receptors on cell membrane. It accelerates uptake of LDL from blood circulation, reduces the concentrations of LDL-choleterol (LDL-c), total cholesterol (TC) and TG in plasma and upregulates plasma high-density lipoprotein cholesterol (HDL-c). The effect of statins on anti-hyperlipidemia varies among individuals. Recently genetic polymorphisms are concerned as an important contribution to the differential effects. The DNAs of 209 hyperlipidemic individuals treated with atorvastatin (ATV) or rosuvastatin (RSV) 10 mg/day were analyzed for twenty-four single nucleotide polymorphisms (SNPs) within genes related to lipid synthesis, transport and metabolism, such as ABCA1, ABCG5/8, APOA5, CETP, FDFT1, LDLR, and genes related to statin disposition, including ABCB1, ABCG2, CYP2C9/2C19, CYP3A5, SLCO1B1. The polymorphisms were examined for the association with baseline lipid profiles and the lipid-lowering effects of ATV and RSV. To extensively study gene polymorphisms and the efficacy of statins, additional forty-eight SNPs were screened within genes of ABCA1, APOA1, APOA5, CETP, LPL, LIPC and PPARA/D/G in patients treated with RSV. Genetic variations, SNPs and haplotypes were further analyzed in terms of the levels of TC, TG, LDL-c, HDL-c and the ratio of TG/HDL and TC/HDL upon RSV therapy. SNPs ABCG2 (rs2231142), APOA5 (rs3135506), CETP (rs708272, rs17245715, rs12597250), LDLR (rs5929), MIA3 (rs17465637) were associated with baseline lipid profiles. There were 2 SNPs, LDLR (rs5925) and LDLR (rs4508523), associated with ATV treatment. On the other side, SNPs ABCG2 (rs2231142), misc (rs501120), PPARA (rs1800234) and PPARG (rs4684847) were significantly associated with the RSV treatment. In haplotype analysis, higher baseline TC and LDL-c were shown in the individuals with least common haplotype C-T-G-G-G-A (frequency: 7.899%) of ABCA1, compared to those with more common haplotypes C-T-G-G-G-G (frequency: 13.177%) and T-T-G-G-G-A (frequency: 12.033%). After RSV therapy, individuals with C-T-G-G-G-A haplotype showed the least elevation of TG concentration (C-T-G-G-G-G：T-T-G-G-G-A：C-T-G-G-G-A，-23.904±24.623%：-20.192±24.596%：0.4781±37.064%，p value= 0.019) and reduction of TG/HDL ratio (C-T-G-G-G-G：T-T-G-G-G-A：C-T-G-G-G-A，-1.015±1.7793：-0.8910±1.3887：-0.2638±1.4789，p value= 0.016) among three haplotypes. This study showed that genetic polymorphisms may play a role in baseline lipid profiles and the lipid-lowering effect of ATV and RSV. Further studies are needed for validation of the results of this study in a larger Taiwanese population.