The good and the bad
The good and the bad
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好的和坏的
DOI：
10.1111/jth.13161
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发表时间：
2015
影响因子：
10.4
通讯作者：
P. Reitsma
中科院分区：
文献类型：
--
作者：
F. Rosendaal;P. Reitsma
虽然疾病通常只带来不适、痛苦和死亡，但有些疾病也有好处。这首先是在遗传性状中发现的。当一种遗传疾病通过导致过早死亡而影响生殖（“健康”）时，有害基因将不会遗传下去。霍尔丹是第一个估计血友病突变率的人，他计算出，为了解释20世纪中期英国血友病患者的数量，所有在1066年诺曼人征服期间活着的男性都必须患有血友病。也就是说，除非患有这种疾病也有一些健康益处，否则可能会出现新的突变。事实证明，血友病确实经常是由于患者或其最近祖先的突变事件而从头开始的。零适应度的遗传性疾病，如霍尔丹时代的血友病，在出生时的患病率完全由突变率决定；因此，这种遗传疾病在全球所有种族群体中都有相同的发病率（事实上，对于先天性疾病，我们需要将疾病的频率表示为患病率，而不是发病率，因为后者要求在一段时间内最初没有患病的人发病，例如血友病出血的年发病率）。当适合度不同于零时，遗传疾病的患病率在不同人群之间往往不同。这些变化的主要驱动因素是随机奠基人效应。这在对适应度影响很小或没有影响的独特突变中最为明显，例如因子V Leiden。这种突变仅发生在3万年前的高加索人祖先身上，因此只在高加索人后裔中发现，在欧洲各地的流行率从1%到15%不等。即使在Leiden因子V的情况下，由于早期血栓形成，每一代都会丢失一些基因，并且需要生存利益来维持患病率平衡。对于factor V Leiden来说，分娩过程中出血量的轻微减少可能就是这种好处。人群之间流行率的差异也可能源于依赖于环境的有益影响。镰状细胞病在非洲和南美洲流行，并且在祖先来自那里的个体中流行，而在北欧人群中很少发现。一个合理的解释是镰状细胞特性（携带）提供了对疟疾的保护。这种选择性优势显然不会在没有疟疾的地区产生任何影响。囊性纤维化的情况几乎相反，这是一种几乎只发生在白种人身上的致命疾病。这样做的好处是减少了霍乱和其他可能的消化系统细菌感染的影响，这些细菌感染增加了这种变体的流行率。在这一期的《血栓与止血》杂志上，Seaman和他的同事报告了一项研究，旨在研究遗传性血管性血友病的选择性益处。通过使用医院出院登记簿，作者可以将5000名血管性血血病患者的疾病代码与近2000万名其他患者的入院情况进行对比。血管性血友病患者动脉心血管疾病（心肌梗死和缺血性卒中）的患病率明显降低。尽管本报告显示了常规登记在研究病因和预后方面的效用，但这些发现远未确定：该研究的设计是横断面的，因为登记通常不是为了研究目的而创建的，因此在诊断分类中可能存在不准确性。此外，在患有某种疾病的患者中，疾病可能优先被误诊。然而，这一有趣的发现与先前发现的血友病，甚至血友病携带者对动脉血栓性疾病发病率的保护作用相吻合。这些有益的影响不太可能影响出血性疾病的流行，因为在不太遥远的过去，患有这些疾病的患者很少能达到从心血管疾病风险降低中获益的年龄。出血性疾病也不太可能影响未来的患病率，因为心血管疾病发生在育龄之后。这也将防止出血性疾病的持续增加，这是由于这种对血栓性疾病的保护。然而，对于个别病人来说，这种好处是额外的。
Although diseases usually only bring discomfort, misery, and death, some also have benefits. This was first recognized in genetic traits. When a genetic disease affects procreation (‘fitness’) by causing premature death, the deleterious genes will not be passed on. Haldane, who was the first to estimate the mutation rate in hemophilia, calculated that, in order to account for the number of hemophilic patients in mid-20th-century England, all males alive during the conquest by the Normans in 1066, must have had hemophilia. That is, unless there is also some health benefit to having the disease, or new mutations can arise. As it turned out, hemophilia does indeed often arise de novo, owing to a mutational event in the patient or his recent ancestry. Genetic disease with zero fitness, as hemophilia was in Haldane’s day, has a prevalence at birth that is fully dictated by the mutation rate; such genetic disease, therefore, occurs across the globe in all ethnic groups with the same prevalence (indeed, for congenital disorders, we need to express the frequency of disease as a prevalence and not an incidence, as the latter requires the occurrence of disease in those who initially did not have it over a certain period of time, e.g. the annual incidence of bleeding in hemophilia). When fitness is different from zero, the prevalence of genetic disorders often varies between populations. The main drivers of these variations are random founder effects. This is most clearly visible in unique mutations with a low or absent effect on fitness, e.g. factor V Leiden. This mutation occurred in a Caucasian ancestor only 30 000 years ago, and hence is only found in Caucasian descendants, with diverging prevalence rates across Europe that range from 1% to 15%. Even in the case of factor V Leiden, some genes will be lost in every generation, owing to early thrombosis, and a survival benefit is needed to maintain the prevalence equilibrium. For factor V Leiden, a mild reduction in blood loss during delivery could be this benefit. Differences in prevalence between populations may also result from beneficial effects that are dependent on the environment. Sickle cell disease is prevalent in Africa and South America, and in individuals whose ancestors hail from there, whereas it is rarely found in more Nordic populations. A plausible explanation is that sickle cell trait (carriership) offers protection against malaria. Such a selective advantage would obviously not have any effect in areas that are clear of malaria. Almost the opposite is seen for cystic fibrosis, a lethal disease that almost exclusively affects Caucasians. Here, the advantage is a reduction of the effects of cholera and possibly other bacterial infections in the digestive system, which has increased the variant’s prevalence. In this issue of the Journal of Thrombosis and Haemostasis, Seaman and colleagues report a study that aimed to examine the selective benefits of inherited von Willebrand disease. By using a register of hospital discharges, the authors could contrast disease codes in > 7500 patients with von Willebrand disease, with nearly 20 million hospital admissions in other patients. The prevalence of arterial cardiovascular disease (myocardial infarction and ischemic stroke) was clearly reduced in patients with von Willebrand disease. Whereas this report shows the utility of routine registers for studying etiology and prognosis, these findings are far from definitive: the study was cross-sectional in design, as registers are often not created for research purposes, thus there may be inaccuracies in the classification of diagnoses. Moreover, diseases may be preferentially misdiagnosed in patients with a certain disorder. Nevertheless, the intriguing finding fits with previous discoveries of a protective effect of hemophilia, and even hemophilia carriership, on the incidence of arterial thrombotic disease. It is unlikely that these beneficial effects will have affected the prevalence of bleeding disorders, because, in the not-so-distant past, patients with these disorders rarely reached an age at which they would profit from a reduced risk of cardiovascular disease. It is also unlikely that bleeding disorders will affect the prevalence in the future, as cardiovascular disease occurs after reproductive age. This will also prevent a continually increasing prevalence of bleeding disorders owing to this protection against thrombotic disease. Nevertheless, for individual patients, the benefit is a bonus.