Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Japan.
Atherosclerosis. 2013 Apr;227(2):373-9. doi: 10.1016/j.atherosclerosis.2013.01.020. Epub 2013 Jan 25.
We previously reported the association of single nucleotide polymorphisms in the lymphotoxin alpha (LTα) gene with susceptibility to acute myocardial infarction (AMI) and increased mortality after discharge. In the present study, we investigated whether the adverse effect of LTα C804A polymorphism on mortality could be pharmacologically modified by statin treatment after AMI.
We conducted a multicenter study that included 3486 post-AMI patients between 1998 and 2008. During a median follow-up period of 1775 days, 247 deaths were recorded. The mortality rate was significantly higher in LTα 804A allele carriers compared to non-804A allele carriers (7.9% vs. 5.7%, p = 0.011). The LTα 804A allele was significantly associated with increased mortality for post-AMI patients not receiving statins (hazard ratio [HR]: 1.48, 95% confidence interval [CI]: 1.03-2.12, p = 0.034), but not for those receiving statins (HR: 1.22, 95% CI: 0.70-2.10, p = 0.486). In-vitro experimental analyses demonstrated that the LTα 804A polymorphic protein, 26Asn-LTα3, induced monocyte-endothelial interaction and endoplasmic reticulum (ER) stress in cardiomyocytes more strongly than the LTα3 804C polymorphic protein 26Thr-LTα3. However, the effects of both LTα3 proteins were decreased and became comparable by the pretreatment of cells with pravastatin.
LTα C804A polymorphism was associated with an increased risk of mortality for AMI patients, although this effect was masked in patients treated with statins. This finding is supported by the observed attenuation of 26Asn-LTα3-mediated monocyte-endothelial interaction and ER stress in cardiomyocytes treated with pravastatin. LTα C804A polymorphism may have potential as a novel therapeutic target for secondary prevention after AMI.
我们之前报道过淋巴毒素α（LTα）基因的单核苷酸多态性与急性心肌梗死（AMI）易感性和出院后死亡率增加有关。在本研究中，我们研究了 AMI 后他汀类药物治疗是否可以在药理学上修饰 LTα C804A 多态性对死亡率的不利影响。
我们进行了一项多中心研究，该研究纳入了 1998 年至 2008 年间的 3486 名 AMI 后患者。在中位数为 1775 天的随访期间，记录了 247 例死亡。与非 804A 等位基因携带者相比，LTα 804A 等位基因携带者的死亡率明显更高（7.9%比 5.7%，p=0.011）。LTα 804A 等位基因与未接受他汀类药物治疗的 AMI 后患者的死亡率增加显著相关（风险比[HR]：1.48，95%置信区间[CI]：1.03-2.12，p=0.034），但与接受他汀类药物治疗的患者无关（HR：1.22，95%CI：0.70-2.10，p=0.486）。体外实验分析表明，LTα 804A 多态性蛋白 26Asn-LTα3 比 LTα3 804C 多态性蛋白 26Thr-LTα3 更能诱导单核细胞-内皮细胞相互作用和心肌细胞内质网（ER）应激。然而，细胞用普伐他汀预处理后，两种 LTα3 蛋白的作用均减弱且变得相当。
LTα C804A 多态性与 AMI 患者的死亡率增加相关，尽管这种影响在接受他汀类药物治疗的患者中被掩盖。这一发现得到了以下观察结果的支持：普伐他汀处理后，26Asn-LTα3 介导的单核细胞-内皮细胞相互作用和 ER 应激在心肌细胞中减弱。LTα C804A 多态性可能成为 AMI 后二级预防的新治疗靶点。
