Polymorphisms in the angiotensin-converting enzyme gene are associated with unipolar depression, ACE activity and hypercortisolism
Polymorphisms in the angiotensin-converting enzyme gene are associated with unipolar depression, ACE activity and hypercortisolism
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DOI：
10.1038/sj.mp.4001884
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发表时间：
2006-11-01
影响因子：
11
通讯作者：
Bondy, B.
中科院分区：
文献类型：
--
作者：
Baghai, T. C.;Binder, E. B.;Bondy, B.
血管紧张素转换酶（ACE）被认为会影响下丘脑-垂体-肾上腺皮质（HPA）系统的活性，该系统在大多数重度抑郁症患者中表现出过度活跃。 ACE 基因已知与心血管疾病相关，而心血管疾病又会增加抑郁症的易感性，因此是情感障碍的一个有前途的候选基因。我们研究了 ACE 基因中 35 个单核苷酸多态性 (SNP) 和插入/缺失 (I/D) 多态性与单相重度抑郁症易感性之间的遗传关联，以及与 ACE 血清活性和 HPA 系统功能参数的遗传关联。对两个独立的病例/对照样本进行了调查，其中共有 843 名不相关的单相抑郁患者和 1479 名健康对照者。筛选病例/对照样本以检测与单相重度抑郁症的遗传关联。此外，还使用复制样本来确认检测到的关联，并进一步研究与抑郁症相关的遗传变异的功能后果。在筛选样本中，ACE 基因内的两个 SNP 与单相重度抑郁症显着相关。我们的复制样本证实了位于 ACE 基因启动子区域的一个 SNP (rs4291) 与单相重度抑郁症的关联。该 SNP 的 T 等位基因与抑郁症相关，抑郁的 T 等位基因携带者表现出较高的 ACE 血清活性和 HPA 轴过度活跃。 ACE 基因的变异体（例如 SNP rs4291）被认为是单相重性抑郁症的易感因素。我们可以证明，SNP rs4291 影响 ACE 活性和 HPA 轴过度活跃，因此可能代表单相抑郁和心血管疾病的常见病理生理联系。
Angiotensin-converting enzyme ( ACE) is assumed to influence the activity of the hypothalamic-pituitary-adrenocortical (HPA) system, which shows hyperactivity in the majority of patients with major depression. The ACE gene, known to be associated with cardiovascular disorders, which in turn are accompanied with an increased susceptibility for depression, is therefore a promising candidate gene for affective disorders. We investigated the genetic association between 35 single-nucleotide polymorphisms ( SNPs) and an insertion/deletion (I/D)-polymorphism in the ACE gene and the susceptibility for unipolar major depression together with the genetic association with ACE serum activity and functional parameters of the HPA system. Two independent case/control samples with a total of 843 unrelated unipolar depressed patients and 1479 healthy controls were investigated. A case/control sample was screened to detect genetic associations with unipolar major depression. In addition, a replication sample was used to confirm the detected associations and to further investigate functional consequences of the genetic variants associated with depression. In the screening sample, two SNPs within the ACE gene were significantly associated with unipolar major depression. The association with unipolar major depression of one SNP (rs4291) located in the promoter region of the ACE gene was confirmed in our replication sample. The T-allele of this SNP was associated with depression and depressed T-allele carriers showed higher ACE serum activity and HPA-axis hyperactivity. Variants of the ACE gene such as SNP rs4291 are suggested susceptibility factors for unipolar major depression. We could show that SNP rs4291 influences ACE activity and HPA-axis hyperactivity and might therefore represent a common pathophysiologic link for unipolar depression and cardiovascular disease.