Genomics of Primary Biliary Cirrhosis

描述（由申请人提供）：原发性胆汁性肝硬化（PBC）是一种自身免疫性肝病，主要影响女性，降低生活质量，尽管使用熊去氧胆酸（UDCA）治疗，但通常导致肝移植。约30%的患者对UDCA治疗无明显反应（即，无应答者），并且倾向于进行性疾病和更差的预后。尽管最近在PBC遗传学领域取得了进展，但我们目前关于PBC发病机制的知识尚未导致有益于PBC患者的新疗法的知情开发。2002年，我们创建了马约诊所PBC遗传流行病学（MCPGE）资源，以更好地了解疾病的遗传和非遗传风险，并旨在改善PBC的预后和治疗。这一持续的资源包括关于疾病进展和结局的广泛临床数据，前瞻性收集的关于生活方式、环境暴露和家族史的问卷数据，以及生物标本，包括DNA、血清、血浆和淋巴母细胞系（LCL）。迄今为止，919名PBC患者和1，043名一级亲属是MCPGE的同意参与者，使其成为北美同类资源中最大的资源。我们还与加拿大PBC队列和英国PBC联盟的研究人员建立了富有成效的合作关系，以分享资源并验证我们共同目标的成果。在过去的5年中，我们在发现和验证目前已知与PBC相关的26个遗传位点中的大多数方面发挥了关键作用，并建立了基因X基因和基因X环境相互作用的范例，这些基因和基因X环境相互作用可以改变PBC风险。然而，从PBC遗传结构的角度来看，与临床结果和疾病病理生物学相关的重要问题仍然没有得到解决，这些问题可能会彻底改变PBC的理解和治疗。在本申请中，我们提出了几个针对我们特定目标的假设：在目标1中，我们将发现并验证影响PBC结局的遗传变异，包括影响UDCA治疗反应和无移植生存期的遗传变异。在目标2中，我们将通过识别和验证新的罕见（目标2a：家族研究）和低效应常见（目标2b：病例对照研究）遗传变异以及遗传相互作用（目标2c：基因X基因，基因X环境研究）来更好地定义PBC的基因组结构，这些遗传相互作用可以解释先前PBC GWAS和精细定位研究中缺失的遗传力。在目标3中，我们将使用患者和对照LCL的RNA测序以及表达和剪接数量性状基因座（eQTL，spQTL）作图来研究所观察到的PBC遗传关联的生物学机制。总的来说，这项研究将进一步加深我们对PBC的遗传变异和疾病机制的理解，对个体化治疗和预后具有有意义的临床影响。

DESCRIPTION (provided by applicant): Primary Biliary Cirrhosis (PBC) is an autoimmune liver disease that affects mainly women, diminishes quality of life, and often leads to liver transplantation despite therapy with ursodeoxycholic acid (UDCA). Some 30% of patients do not respond robustly to UDCA therapy (i.e., non-responders) and tend towards progressive disease and worse prognosis. Notwithstanding recent progress in the field of PBC genetics, our current knowledge regarding PBC pathogenesis has not led to informed development of novel therapies to benefit PBC patients. In 2002, we created the Mayo Clinic PBC Genetic Epidemiology (MCPGE) Resource to better understand the genetic and non-genetic risks of the disease, and aimed at improving the prognosis and therapy of PBC. This ongoing resource comprises of extensive clinical data on disease progression and outcomes, prospectively collected questionnaire data regarding life-styles, environmental exposures, and family history, as well as biospecimens including DNA, serum, plasma, and lymphoblastoid cell-lines (LCLs). To date, 919 PBC patients and 1,043 first-degree relatives are consenting participants in the MCPGE, making it the largest resource of its kind in North America. We have also established productive collaborations with investigators of the Canadian PBC cohort and the UK PBC Consortium to share resources and validate results in the interest of our common goals. Over the past 5 years we have played a key role in discovering and validating a majority of the 26 genetic loci currently known to be associated with PBC, and established paradigms of gene X gene and gene X environment interactions, which modify PBC risk. Yet, important questions from the standpoint of PBC genetic architecture related to clinical outcomes and disease pathobiology that could revolutionize the understanding and therapy of PBC remain untapped. In this application, we propose to test several hypotheses addressing our Specific Aims: In Aim 1 we will discover and validate genetic variants that impact PBC outcomes, including those affecting response to UDCA therapy and transplant-free survival. In Aim 2 we will better define the genomic architecture of PBC through identification and validation of novel rare (Aim 2a: familial studies) and low-effect common (Aim 2b: case-control studies) genetic variants, as well as genetic interactions (Aim 2c: gene X gene, gene X environment studies) that could explain the missing heritability from prior PBC GWAS and fine mapping studies. In, Aim 3 we will start examining biological mechanisms underlying observed PBC genetic associations using RNA sequencing of patient and control LCLs and expression and splicing quantitative trait locus (eQTL, spQTL) mapping. Overall, this study will further our understanding of genetic variants and disease mechanisms of PBC that have meaningful clinical impact on individualizing therapy and prognosis.