Genomics of Primary Biliary Cirrhosis

描述(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，但经常导致肝移植。约30%的患者对UDCA治疗反应不强烈(即无反应者)，并倾向于疾病进展和更差的预后。尽管最近在PBC遗传学领域取得了进展，但我们目前对PBC发病机制的了解并没有导致新的治疗方法的发展，使PBC患者受益。2002年，我们创建了梅奥诊所PBC遗传流行病学(MCPGE)资源，以更好地了解该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果的广泛临床数据，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，以及包括DNA、血清、血浆和淋巴母细胞系(LCL)在内的生物标本。到目前为止，已有919名PBC患者和1043名一级亲属同意参加MCPGE，使其成为北美同类资源中最大的。我们还与加拿大建设和平委员会队列和英国建设和平委员会联合会的调查人员建立了富有成效的合作，为了我们的共同目标共享资源和验证结果。在过去的5年里，我们在发现和验证目前已知的与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X基因和X基因环境交互作用的范例，这些交互作用改变了PBC的风险。然而，从PBC遗传结构的角度来看，可能彻底改变对PBC的理解和治疗的重要问题仍未得到解决，这些问题与临床结果和疾病病理生物学有关。在这项应用中，我们建议测试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结局的基因变异，包括那些影响UDCA治疗反应和非移植存活的基因变异。在目标2中，我们将通过鉴定和验证新的罕见(目标2a：家族性研究)和低效常见(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)，更好地定义PBC的基因组结构，这可以解释先前PBC GAs和精细定位研究中缺失的遗传性。在目标3中，我们将开始使用患者和对照LCL的RNA测序以及表达和剪接数量性状基因座(eQTL，spQTL)定位来研究观察到的PBC遗传关联的生物学机制。总之，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，这些因素对个体化治疗和预后具有重要的临床影响。

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.