The Ile164 β2-adrenergic receptor polymorphism adversely affects the outcome of congestive heart failure
The Ile164 β2-adrenergic receptor polymorphism adversely affects the outcome of congestive heart failure
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DOI：
10.1172/jci4059
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发表时间：
1998-10-15
影响因子：
15.9
通讯作者：
Walsh, RA
中科院分区：
文献类型：
--
作者：
Liggett, SB;Wagoner, LE;Walsh, RA
β 2肾上腺素能受体（β 2 AR）是心脏变力性和变时性的重要调节因子，在人群中具有显著的遗传异质性。由于功能障碍的β AR在心力衰竭的发病机制中起作用，我们检验了β 2 AR多态性改变充血性心力衰竭结局的假设。对259例因缺血性或扩张型心肌病导致NYHA心功能III-IV级心力衰竭的患者进行基因分型和前瞻性随访，终点定义为死亡或心脏移植。同时比较了该组与212名健康对照者的等位基因频率，两组间无差异。然而，Ile 164多态性与野生型Thr在此位置的患者相比，其生存率有显著差异，死亡或心脏移植的相对风险为4.81（P < 0.001）。年龄、种族、性别、功能分类、病因学、射血分数和药物使用在这些个体和野生型β 2 AR个体之间没有差异，因此164位的β 2 AR基因型是两组之间唯一明确的区别特征。Ile 164患者的1年生存率为42%，而携带野生型β 2 AR的患者为76%。相反，在氨基酸位置16（精氨酸或甘氨酸）或27（谷氨酰胺或谷氨酸），也改变受体表型的多态性，似乎没有心力衰竭的过程中的影响。结合基于细胞和转基因小鼠的结果，本研究建立了一个范例，即关键信号传导元件的遗传变异体在疾病背景下可能产生病理生理后果。此外，Ile 164多态性和心力衰竭的患者可能是早期积极干预或心脏移植的候选人。
The beta(2)-adrenergic receptor (beta(2)AR), an important modulator of cardiac inotropy and chronotropy, has significant genetic heterogeneity in the population. Because dysfunctional beta ARs play a role in the pathogenesis of the failing ventricle, we tested the hypothesis that beta(2)AR polymorphisms alter the outcome of congestive heart failure. 259 patients with NYHA functional class Ill-IV heart failure due to ischemic or dilated cardiomyopathy were genotyped and prospectively followed, with the endpoint defined as death or cardiac transplantation. The allele frequencies between this group and those of 212 healthy controls also were compared and did not differ between the groups. However, those with the Ile164 polymorphism displayed a striking difference in survival with a relative risk of death or cardiac transplant of 4.81 (P < 0.001) compared with those with the wild-type Thr at this position. Age, race, gender, functional class, etiology, ejection fraction, and medication use did not differ between these individuals and those with the wildtype beta(2)AR, and thus the beta(2)AR genotype at position 164 was the only clear distinguishing feature between the two groups. The 1-yr survival for Ile164 patients was 42% compared with 76% for patients harboring wild-type beta(2)AR. In contrast, polymorphisms at amino acid positions 16 (Arg or Gly) or 27 (Gln or Glu), which also alter receptor phenotype, did not appear to have an influence on the course of heart failure. Taken together with cell-based and transgenic mouse results, this study establishes a paradigm whereby genetic variants of key signaling elements can have patho-physiologic consequences within the context of a disease. Furthermore, patients with the Ile164 polymorphism and heart failure may be candidates for earlier aggressive intervention or cardiac transplantation.