Mutations in complement regulatory proteins predispose to preeclampsia: a genetic analysis of the PROMISSE cohort.
Mutations in complement regulatory proteins predispose to preeclampsia: a genetic analysis of the PROMISSE cohort.
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DOI：
10.1371/journal.pmed.1001013
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发表时间：
2011-03
期刊：
影响因子：
15.8
通讯作者：
Atkinson JP
中科院分区：
文献类型：
--
作者：
Salmon JE;Heuser C;Triebwasser M;Liszewski MK;Kavanagh D;Roumenina L;Branch DW;Goodship T;Fremeaux-Bacchi V;Atkinson JP
Jane Salmon及其同事研究了250例SLE和/或抗磷脂抗体孕妇，发现在子痫前期患者和无自身免疫性疾病的子痫前期患者中补体调节蛋白的风险变异存在关联。患有系统性红斑狼疮（SLE）或抗磷脂抗体（APL Ab）（以补体介导损伤为特征的自身免疫性疾病）的妇女妊娠与子痫前期和流产的风险增加相关。我们之前在小鼠身上的研究表明，针对胎盘的补体激活会导致血管生成失衡和胎盘功能不全。我们使用promise，一项针对250例SLE和/或APL Ab孕妇的前瞻性研究，来验证人类限制补体激活能力受损易导致子痫前期的假设。我们对40例先兆子痫患者中编码三种补体调节蛋白（膜辅助因子蛋白（MCP）、补体因子I （CFI）和补体因子H (CFH)）的基因进行了测序，发现其中7例（18%）存在杂合突变。这些患者中有5例具有MCP或CFI的风险变异，这些变异先前在非典型溶血性尿毒症综合征（一种以内皮损伤为特征的疾病）中被发现。其中一个在MCP中有一个新的突变，损害了C4b的调节。据我们所知，这些发现构成了SLE和/或APL Ab中与子痫前期相关的第一个遗传缺陷。我们在一组非自身免疫性子痫前期患者中证实了MCP和CFI的亚型变异的关联，其中59例患者中有5例是杂合突变。发生子痫前期的SLE和/或APL Ab患者以及缺乏自身免疫性疾病的子痫前期患者中补体调节蛋白风险变异的存在，将补体激活与疾病发病机制联系起来，并提出了治疗这一重要公共卫生问题的新靶点。大多数怀孕最终会生下一个健康的婴儿，但令人遗憾的是，大约四分之一的妇女在怀孕期间失去了孩子。子痫前期是一种常见的与妊娠有关的医学问题，它会威胁到婴儿和母亲的生命。轻度和重度先兆子痫分别影响10%和1%-2%的孕妇。先兆子痫的发生是由于胎盘的功能出现问题，胎盘是将营养和氧气从母亲输送给婴儿并清除婴儿体内废物的器官。虽然先兆子痫在妊娠早期就开始了，但在妊娠20周后，通过高血压（hypertension）和尿中出现蛋白质（proteinuria）来诊断。其他警告信号包括头痛、手和脸肿胀。治疗先兆子痫的唯一方法是分娩，通常是早期引产，以防止子痫（癫痫）、中风、肝肾衰竭以及母亲的呼吸和血管问题。虽然一般不建议在怀孕37周之前分娩，但在先兆子痫的情况下，继续怀孕对婴儿和母亲来说都太危险了。不幸的是，当严重的先兆子痫发生在妊娠中期时，出生的婴儿体重只有500克，他们可能无法存活。由于先兆子痫的确切原因尚不清楚，因此很难开发治疗方法或找到预防方法。许多专家认为免疫系统的问题——特别是补体激活的紊乱——可能与子痫前期有关。补体系统是一组血液蛋白，用来攻击入侵的细菌和病毒。补体蛋白的激活通常受到严格调控（补体系统的过度激活会导致组织损伤），由于子痫前期可能有家族遗传，一种假设是补体调节蛋白的突变（基因改变）可能使女性易患子痫前期。在这项研究中，研究人员通过对患有自身免疫性疾病系统性红斑狼疮（SLE）和/或抗磷脂抗体（APL Ab）的孕妇进行编码补体调节蛋白的基因测序来验证这一假设。在自身免疫性疾病中，免疫系统攻击健康的人体细胞，而不是有害的入侵者。SLE和APL Ab都以补体介导的组织损伤为特征，并与子痫前期和流产的风险增加相关。250名SLE和/或APL抗体患者在怀孕12周时被纳入promise研究（一项多中心观察性研究，旨在确定SLE和/或APL抗体患者妊娠结局的预测因素），并随访整个妊娠期。30名患者在研究期间出现了先兆子痫，另有10名患者在之前的怀孕期间患有先兆子痫。研究人员对这40名患者的补体调节蛋白基因进行了测序：膜辅助因子蛋白（MCP）、因子I和因子H。7名女性（18%）在其中一种基因的一个拷贝中发生突变（人类细胞中大多数基因有两个拷贝）。五个突变是MCP或因子I的改变，这些基因变异增加了溶血性尿毒症综合征（一种以血管损伤为特征的疾病）的风险。第六个突变是一个新的MCP突变，它损害了MCP调节补体组分C4b的能力。最后的突变是因子H突变，没有任何明显的功能影响。在34名没有子痫前期的配对参与者中，没有发现补体调节蛋白突变，但在一组妊娠期间发生子痫前期的非自身免疫性女性中，10%的人有MCP或因子I突变。这些发现确定了MCP和因子I突变是与SLE和/或APL Ab孕妇子痫前期相关的遗传缺陷。他们还揭示了类似突变与没有任何潜在自身免疫性疾病的女性子痫前期之间的联系。结合先前动物实验的证据，这些发现表明补体激活失调参与了先兆子痫的发展。虽然需要进一步的研究来证实和扩展这些发现，但这些结果表明，参与补体活化调节的蛋白质可能是治疗子痫前期的新靶点，并提高了开发检测来识别有子痫前期风险的妇女的可能性。请通过本摘要的在线版本http://dx.doi.org/10.1371/journal.pmed.1001013访问这些网站。Tommy's是一家英国慈善机构，为流产、早产和死胎的病因和预防进行科学研究提供资金，该机构有先兆子痫的相关信息。March of dime基金会是一家致力于怀孕和婴儿健康的非营利组织，它有先兆子痫的相关信息。英国国家卫生服务选择网站也有先兆子痫的相关信息。关于子痫前期（请注意，维基百科是一个免费的在线百科全书，任何人都可以编辑；有几种语言版本）关于promise研究的更多信息可以在这里找到
Jane Salmon and colleagues studied 250 pregnant patients with SLE and/or antiphospholipid antibodies and found an association of risk variants in complement regulatory proteins in patients who developed preeclampsia, as well as in preeclampsia patients lacking autoimmune disease. Pregnancy in women with systemic lupus erythematosus (SLE) or antiphospholipid antibodies (APL Ab)—autoimmune conditions characterized by complement-mediated injury—is associated with increased risk of preeclampsia and miscarriage. Our previous studies in mice indicate that complement activation targeted to the placenta drives angiogenic imbalance and placental insufficiency. We use PROMISSE, a prospective study of 250 pregnant patients with SLE and/or APL Ab, to test the hypothesis in humans that impaired capacity to limit complement activation predisposes to preeclampsia. We sequenced genes encoding three complement regulatory proteins—membrane cofactor protein (MCP), complement factor I (CFI), and complement factor H (CFH)—in 40 patients who had preeclampsia and found heterozygous mutations in seven (18%). Five of these patients had risk variants in MCP or CFI that were previously identified in atypical hemolytic uremic syndrome, a disease characterized by endothelial damage. One had a novel mutation in MCP that impairs regulation of C4b. These findings constitute, to our knowledge, the first genetic defects associated with preeclampsia in SLE and/or APL Ab. We confirmed the association of hypomorphic variants of MCP and CFI in a cohort of non-autoimmune preeclampsia patients in which five of 59 were heterozygous for mutations. The presence of risk variants in complement regulatory proteins in patients with SLE and/or APL Ab who develop preeclampsia, as well as in preeclampsia patients lacking autoimmune disease, links complement activation to disease pathogenesis and suggests new targets for treatment of this important public health problem. ClinicalTrials.gov NCT00198068 Please see later in the article for the Editors' Summary Most pregnancies culminate in the birth of a healthy baby but, sadly, about a quarter of women lose their babies during pregnancy. A common pregnancy-related medical problem that threatens the life of both baby and mother is preeclampsia. Mild and severe preeclampsia affects up to 10% and 1%–2% of pregnancies, respectively. Preeclampsia occurs because of a problem with the function of the placenta, the organ that transfers nutrients and oxygen from mother to baby and removes waste products from the baby. Although preeclampsia begins early in pregnancy, it is diagnosed by the onset of high blood pressure (hypertension) and the appearance of protein in the urine (proteinuria) after 20 weeks of pregnancy. Other warning signs include headaches and swelling of the hands and face. The only cure for preeclampsia is delivery, and labor is usually induced early to prevent eclampsia (seizures), stroke, liver and kidney failure, and breathing and blood vessel problems developing in the mother. Although delivery before 37 weeks of pregnancy is not generally recommended, in cases of preeclampsia it may be too dangerous for both the baby and the mother to allow the pregnancy to continue. Unfortunately when severe preeclampsia occurs in the second trimester, babies weighing only 500 grams may be delivered and they may not survive. Because the exact cause of preeclampsia is unknown, it is difficult to develop treatments for the condition or to find ways to prevent it. Many experts think that immune system problems—in particular, perturbations in complement activation—may be involved in preeclampsia. The complement system is a set of blood proteins that attacks invading bacteria and viruses. The activation of complement proteins is usually tightly regulated (overactivation of the complement system causes tissue damage) and, because preeclampsia may run in families, one hypothesis is that mutations (genetic changes) in complement regulatory proteins might predispose women to preeclampsia. In this study, the researchers test this hypothesis by sequencing genes encoding complement regulatory proteins in pregnant women with the autoimmune diseases systemic lupus erythematosus (SLE) and/or antiphospholipid antibodies (APL Ab) who developed preeclampsia. In autoimmune diseases, the immune system attacks healthy human cells instead of harmful invaders. Both SLE and APL Ab are characterized by complement-mediated tissue injury and are associated with an increased risk of preeclampsia and miscarriage. Two hundred fifty women with SLE and/or APL Ab were enrolled into the PROMISSE study (a multi-center observational study to identify predictors of pregnancy outcome in women with SLE and/or APL Ab) when they were 12 weeks pregnant and followed through pregnancy. Thirty patients developed preeclampsia during the study and ten more had had preeclampsia during a previous pregnancy. The researchers sequenced the genes for complement regulatory proteins: membrane cofactor protein (MCP), factor I, and factor H in these 40 patients. Seven women (18%) had mutations in one copy of one of these genes (there are two copies of most genes in human cells). Five mutations were alterations in MCP or factor I that are gene variants that increase the risk of hemolytic uremic syndrome, a disease characterized by blood vessel damage. The sixth mutation was a new MCP mutation that impaired MCP's ability to regulate complement component C4b. The final mutation was a factor H mutation that did not have any obvious functional effect. No mutations in complement regulatory proteins were found in 34 matched participants in PROMISSE without preeclampsia but, among a group of non-autoimmune women who developed preeclampsia during pregnancy, 10% had mutations in MCP or factor I. These findings identify MCP and factor I mutations as genetic defects associated with preeclampsia in pregnant women with SLE and/or APL Ab. Importantly, they also reveal an association between similar mutations and preeclampsia in women without any underlying autoimmune disease. Taken together with evidence from previous animal experiments, these findings suggest that dysregulation of complement activation is involved in the development of preeclampsia. Although further studies are needed to confirm and extend these findings, these results suggest that proteins involved in the regulation of complement activation could be new targets for the treatment of preeclampsia and raise the possibility that tests could be developed to identify women at risk of developing preeclampsia. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001013. Tommy's, a UK charity that funds scientific research into the causes and prevention of miscarriage, premature birth, and stillbirth, has information on preeclampsia The March of Dimes Foundation, a nonprofit organization for pregnancy and baby health, has information on preeclampsia The UK National Health Services Choices website also has information about preeclampsia Wikipedia has pages on the complement system, on autoimmune disease, and on preeclampsia (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages) More information on the PROMISSE study is available
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