Genetic profiling of fatty acid desaturase polymorphisms identifies patients who may benefit from high-dose omega-3 fatty acids in cardiac remodeling after acute myocardial infarction—Post-hoc analysis from the OMEGA-REMODEL randomized controlled trial

Background
The double-blind OMEGA-REMODEL placebo-controlled randomized trial of high-dose omega-3 fatty acids (O-3FA) post-acute myocardial infarction (AMI) reported improved cardiac remodeling and attenuation of non-infarct myocardial fibrosis. Fatty acid desaturase 2 (FADS2) gene cluster encodes key enzymes in the conversion of essential omega-3 and omega-6 fatty acids into active arachidonic (ArA) and eicosapentaenoic acids (EPA), which influence cardiovascular outcomes.
Methods and results
We tested the hypothesis that the genotypic status of FADS2 (rs1535) modifies therapeutic response of O-3FA in post-AMI cardiac remodeling in 312 patients. Consistent with known genetic polymorphism of FADS2, patients in our cohort with the guanine-guanine (GG) genotype had the lowest FADS2 activity assessed by arachidonic acid/linoleic acid (ArA/LA) ratio, compared with patients with the adenine-adenine (AA) and adenine-guanine (AG) genotypes (GG:1.62±0.35 vs. AA: 2.01±0.36, p<0.0001; vs. AG: 1.76±0.35, p = 0.03). When randomized to 6-months of O-3FA treatment, GG patients demonstrated significant lowering of LV end-systolic volume index (LVESVi), N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and galectin-3 levels compared to placebo (-4.4 vs. 1.2 ml/m2, -733 vs. -181 pg/mL, and -2.0 vs. 0.5 ng/mL; p = 0.006, 0.006, and 0.03, respectively). In contrast, patients with either AA or AG genotype did not demonstrate significant lowering of LVESVi, NT-proBNP, or galectin-3 levels from O-3FA treatment, compared to placebo. The odds ratios for improving LVESVi by 10% with O-3FA treatment was 7.2, 1.6, and 1.2 in patients with GG, AG, and AA genotypes, respectively.
Conclusion
Genetic profiling using FADS2 genotype can predict the therapeutic benefits of O-3FA treatment against adverse cardiac remodeling during the convalescent phase of AMI.
Clinical trial registration information
clinicaltrials.gov Identifier: NCT00729430.

背景
一项针对急性心肌梗死（AMI）后患者的高剂量ω-3脂肪酸（O-3FA）OMEGA-REMODEL双盲安慰剂对照随机试验此前报道称，该治疗可改善心脏重构，并减轻非梗死区心肌纤维化。脂肪酸去饱和酶2（FADS2）基因簇编码关键酶类，可将必需ω-3与ω-6脂肪酸转化为活性花生四烯酸（ArA）与二十碳五烯酸（EPA），上述过程可影响心血管结局。

方法与结果
本研究纳入312例患者，验证如下假说：脂肪酸去饱和酶2（FADS2）基因rs1535位点的基因型状态，可调节急性心肌梗死后患者接受ω-3脂肪酸治疗的心脏重构应答水平。
与已知的FADS2基因多态性特征一致：相较于携带腺嘌呤-腺嘌呤（AA）与腺嘌呤-鸟嘌呤（AG）基因型的患者，本队列中携带鸟嘌呤-鸟嘌呤（GG）基因型的患者，其FADS2活性以花生四烯酸/亚油酸（ArA/LA）比值评估最低（GG组：1.62±0.35 较 AA组：2.01±0.36，p<0.0001；较 AG组：1.76±0.35，p=0.03）。
将患者随机分配接受6个月的ω-3脂肪酸治疗或安慰剂治疗后，GG基因型患者的左心室收缩末期容积指数（LVESVi）、N末端脑钠肽前体（NT-proBNP）及半乳糖凝集素-3水平较安慰剂组显著改善：治疗组的指标变化值分别为-4.4 ml/m²、-733 pg/mL、-2.0 ng/mL，安慰剂组则分别为1.2 ml/m²、-181 pg/mL、0.5 ng/mL；对应p值分别为0.006、0.006和0.03。与之相反，AA或AG基因型患者接受ω-3脂肪酸治疗后，上述三项指标相较于安慰剂组均未出现显著改善。
接受ω-3脂肪酸治疗后，GG、AG及AA基因型患者的左心室收缩末期容积指数降低10%的比值比分别为7.2、1.6和1.2。

结论
通过检测FADS2基因型进行基因分型，可预测急性心肌梗死恢复期患者接受ω-3脂肪酸治疗时，对抗不良心脏重构的治疗获益。

临床试验注册信息
clinicaltrials.gov注册号：NCT00729430。