Maternal-Fetal HLA Sharing and Risk of Preeclampsia

母婴 HLA 共享和先兆子痫的风险

• 批准号: 6636893
• 负责人: AUDREY FRIEDA SAFTLAS
• 金额: $ 54.02万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6636893
• 关键词: cardiovascular disorder epidemiology; clinical research; contraceptives; disease /disorder proneness /risk; embryo /fetus antigen; embryo implantation; female; gene environment interaction; histocompatibility; histocompatibility antigens; human subject; immune tolerance /unresponsiveness; immunopathology; infant human (0-1 year); parents; preeclampsia; women's health

An accumulating body of epidemiological evidence points coherently toward an immune-based etiology for preeclampsia. Several recent studies, as well as a collection of other studies conducted over the past 25 years, suggest that exposure to paternal, fetal; or foreign antigens is protective against subsequent risk preeclampsia; and that paternal/fetal factors may be as important as maternal factors in the etiology of preeclampsia. Consistent this evidence, HLA-sharing between mother and fetus has been positively associated with risk of preeclampsia. We hypothesize that histocompatibility between mother and fetus may have a detrimental effect on pregnancy by impairing maternal recognition of the fetal allograft as a gestation, thereby compromising development of maternal immune tolerance and effective implantation of the placenta. To evaluate this hypothesis, we propose to conduct a case-control study to determine if nulliparous women who develop preeclampsia are more likely to share HLA antigens with their infants than women who have normotensive gestations. Specifically, we will examine sharing at each of five HLA loci (A, B, C, DR, and DQ), as well as generalized sharing across loci. In addition, we will evaluate selected epidemiologic factors indicative of exposure to paternal/fetal antigens (e.g., duration of sexual cohabitation, coital frequency, and use of barrier contraception with baby's father prior to conception). We will also test for the presence of gene-environment interactions to determine if effects of maternal-fetal HLA sharing are modified by the primary epidemiologic exposures under study. The study population (N=250 cases; N=250 controls), identified from Iowa and Connecticut live birth files, will include residents of four Iowa and two Connecticut counties who deliver between November l, 2001 and October 31, 2003. All participants will be asked to provide buccal cell samples from their babies and themselves for HLA genotyping (N=1,000 samples), and to respond to a 25 minute telephone interview. Medical chart abstractions will be conducted to validate case definition and control criteria. The study was powered to detect a two-fold increased risk of preeclampsia associated with the presence of only one maternal- fetal HLA mismatch across the three loci (HLA-A, B, and DRbeta1) loci, with at least 80 percent power, and an alpha of.05. The proposed study may be the first to examine the effects of maternal-fetal HLA sharing in an adequately powered epidemiological framework.

越来越多的流行病学证据一致表明先兆子痫的病因是基于免疫的。最近的几项研究以及过去 25 年进行的一系列其他研究表明，接触父亲、胎儿；或外来抗原可以预防随后的先兆子痫风险；在先兆子痫的病因学中，父亲/胎儿因素可能与母亲因素一样重要。 与此证据一致的是，母亲和胎儿之间的 HLA 共享与先兆子痫的风险呈正相关。 我们假设母亲和胎儿之间的组织相容性可能会损害母体对胎儿同种异体移植物作为妊娠的识别，从而损害母体免疫耐受的发展和胎盘的有效植入，从而对妊娠产生不利影响。 为了评估这一假设，我们建议进行一项病例对照研究，以确定患有先兆子痫的未产妇是否比妊娠正常的妇女更有可能与婴儿共享 HLA 抗原。 具体来说，我们将检查五个 HLA 位点（A、B、C、DR 和 DQ）中每个位点的共享，以及跨位点的广义共享。 此外，我们将评估表明接触父亲/胎儿抗原的选定流行病学因素（例如，同居持续时间、性交频率以及受孕前与婴儿父亲使用屏障避孕措施）。 我们还将测试基因-环境相互作用的存在，以确定母婴 HLA 共享的影响是否会因所研究的主要流行病学暴露而改变。 从爱荷华州和康涅狄格州活产档案中确定的研究人群（N = 250 例；N = 250 对照）将包括在 2001 年 11 月 1 日至 2003 年 10 月 31 日期间分娩的爱荷华州四个县和康涅狄格州两个县的居民。被要求提供婴儿和自己的口腔细胞样本进行 HLA 基因分型（N=1,000 个样本），并接受 25 分钟的电话采访。 将进行病历摘要以验证病例定义和控制标准。 该研究的功效是检测出与三个基因座（HLA-A、B 和 DRbeta1）中仅存在一个母胎 HLA 不匹配相关的先兆子痫风险增加两倍，功效至少为 80%，并且α 为 05。 拟议的研究可能是第一个在充分有力的流行病学框架中检验母婴 HLA 共享影响的研究。