NHLBI TOPMed: My Life Our Future (MLOF) Research Repository of Patients with Hemophilia A (Factor VIII Deficiency) or Hemophilia B (Factor IX Deficiency)

Hemophilia A and B are X-linked bleeding disorders resulting from a deficiency in coagulation factor VIII (FVIII) or factor IX (FIX), respectively. Hemophilia affects approximately 1/5000 male births worldwide, and results in premature death and disability due to bleeding if coagulation factor replacement therapy is not used effectively. Hemophilia is clinically categorized by coagulation factor activity levels and ranges in severity from mild (6% to 30%) to moderate (1-5%) to severe (<1%). Many female "carriers" of hemophilia also have decreased factor activity and morbidity from bleeding. Hemophilia A and B are almost always caused by identifiable mutations in the F8 and F9 genes, respectively, and these mutations are found throughout the structural genes. Although the hemophilias are monogenic disorders, there are wide variations in disease severity and therapeutic outcomes which are not readily explained by the disease causing mutations alone.

The My Life Our Future (MLOF) project ([www.mylifeourfuture.org](http://www.mylifeourfuture.org)) is a national resource developed by a partnership of BloodworksNW (BWNW, formerly the Puget Sound Blood Center), the American Thrombosis and Hemostasis Network (ATHN), the National Hemophilia Foundation (NHF) and Bioverativ, to provide free F8 and F9 gene variant analysis to patients with hemophilia A or B, and to establish a research repository of DNA sequence, DNA, RNA, buffy coat, serum and plasma. The sequence analysis and serum samples are linked to a phenotypic database hosted by ATHN, with samples submitted and clinical data entered at ~100 hemophilia treatment centers (HTCs) nationwide. (See ATHN Research Report Brief in the resource center at [www.athn.org](http://www.athn.org)). MLOF has become the largest hemophilia genetic project worldwide.

The roles of the MLOF partners are: BWNW, to serve as the central laboratory for the project and house the research repository; ATHN, to support and provide the administrative link with HTCs, to facilitate the collection of accurate phenotypic data, to conduct research review and approval for use of the repository and with BWNW to provide samples and data for research projects; NHF, to provide consumer education and facilitate consumer input into the project; and Bioverativ, to provide financial support and scientific input. The project is governed by a Steering Committee consisting of one representative from each organization.

Subject samples chosen from the MLOF parent study for TOPMed and WGS were drawn from those who gave (or parents gave) informed consent for the Research Repository and included patients of all severities and type, but with an emphasis on those with severe hemophilia and others at increased risk of neutralizing antibody (inhibitor) formation and who had samples in the Research Repository (plasma, serum, RNA) for potential additional -omic studies. Also included were samples from subjects where a likely causative variant for hemophilia was not found in the F8 or F9 coding region, intron-exon boundaries or immediate upstream and downstream regions. Since hemophilia is an X-linked disorder, the majority of subjects are male. Racial distribution is similar to the overall population distribution.

血友病A与血友病B均为X连锁出血性疾病，分别因凝血因子VIII（FVIII）或凝血因子IX（FIX）缺乏引发。全球范围内，血友病的发病率约为每5000名男性活产儿中1例；若未有效开展凝血因子替代治疗，患者可因反复出血出现过早死亡与残疾。
血友病临床以凝血因子活性水平进行分型，疾病严重程度可分为轻度（6%~30%）、中度（1%~5%）及重度（＜1%）。多数女性血友病携带者亦存在凝血因子活性降低，并因出血出现临床病症。血友病A与血友病B几乎均由F8及F9基因的可识别突变所致，此类突变广泛分布于整条结构基因中。尽管血友病属于单基因遗传病，但其疾病严重程度与治疗结局存在显著异质性，仅以致病突变无法完全阐释此类差异。
“我的人生，我们的未来”（My Life Our Future, MLOF）项目（http://www.mylifeourfuture.org）是由BloodworksNW（BWNW，前身为普吉特海湾血液中心）、美国血栓与止血网络（American Thrombosis and Hemostasis Network, ATHN）、全国血友病基金会（National Hemophilia Foundation, NHF）及Bioverativ合作打造的国家级资源平台，旨在为血友病A或血友病B患者提供免费的F8及F9基因变异分析服务，并建立涵盖DNA序列、DNA样本、RNA样本、血沉棕黄层、血清及血浆的研究样本库。该项目的序列分析结果与血清样本均与ATHN托管的表型数据库相关联，样本提交与临床数据录入工作在全美约100家血友病治疗中心（hemophilia treatment centers, HTCs）开展。详见ATHN研究报告简报，可登录http://www.athn.org访问其资源中心。目前，MLOF已成为全球规模最大的血友病遗传学研究项目。
各合作方的职责分工如下：BWNW作为项目核心实验室，负责管理研究样本库；ATHN负责搭建与血友病治疗中心的行政联络渠道并提供支持，协助收集精准的表型数据，对样本库的使用开展研究审查与审批工作，并与BWNW协作提供研究项目所需的样本与数据；NHF负责面向患者群体开展健康宣教，并协助患者参与项目决策；Bioverativ负责提供资金支持与科学指导。本项目由指导委员会进行管理，委员会成员由各合作方各选派1名代表组成。
本次用于跨组学精准医学项目（Trans-Omics for Precision Medicine, TOPMed）及全基因组测序（whole genome sequencing, WGS）的受试者样本，均取自MLOF核心研究中已（或其法定监护人已）签署研究样本库知情同意书的受试者，涵盖所有严重程度与类型的血友病患者，但重点纳入重度血友病患者、存在中和抗体（抑制剂）形成高风险的患者，且其研究样本库中留存有血浆、血清、RNA样本以供潜在的多组学研究使用。此外，样本还纳入了那些在F8或F9基因的编码区、内含子-外显子剪接边界及紧邻的上下游区域中未检出疑似致病变异的受试者。由于血友病为X连锁遗传病，绝大多数受试者为男性；该队列的种族分布与总体人群分布基本一致。