慢性乙型病毒性肝炎相关低频/罕见遗传变异和拷贝数目变异的第Ⅱ期研究

慢性乙型病毒性肝炎（乙肝）是多基因复杂性疾病。宿主的遗传背景在乙肝的易感性上起重要作用。本课题组在乙肝相关遗传变异的第Ⅰ期研究中首先在国际上报导了4个相关的低频/罕见遗传变异（Hepatology 2012;56:1661-1670）（影响因子12.003）。现本课题组拟开展乙肝相关基因的第Ⅱ期研究。我们已对另外49例病例及另外50例对照进行了全外显子组测序；并对其中4例进行了全基因组测序；筛选了21个候选基因及4个候选拷贝数目变异,全为国际上尚未报导过的基因/拷贝数目变异。我们已收集到2029例病例，1896例未注射过乙肝疫苗或注射状态不明的对照。现拟在我们的cohort中进一步筛选乙肝相关低频/罕见遗传变异及拷贝数目变异。第Ⅱ期研究是我们第Ⅰ期研究的深入及延续，我们预期会获得好的进一步的结果，这些结果不仅会加深我们对乙肝发病机理的认识，并可能有有个体化治疗上的应用潜能。

Chronic hepatitis B (CHB) is a polygenic, multifactorial disease. Genetic background plays an important role in the susceptibility to the disease. In the search of the susceptible genes, much efforts have been delivered into common genetic variations (frequency >5%). However it has been confirmed that less frequent/rare variations (frequency <5%) usually confers stronger phenotypic effects, but are extremely heterogeneous. This feature of the rare/less frequent alleles determined the selection of the candidates have to be performed in different phases of discovery groups.Our team is the first reported four less frequent/rare genetic variations associated with the susceptibility to the disease (Hepatology 2012;56:1661-1670)(impact factor 12.003). However the extreme heterogeneity of the less frequent/rare variations clearly shows that there are much more associated variations have not been unraveled. Modeling the progression of the international HapMap and the 1000 genome project by different phases, we propose to conduct the second phase of the project. We have further performed exom sequencing in another 49 CHB cases and 50 controls subjects, and the whole genome sequencing in 3 cases and 1 control. We selected 21 candidates less frequent/rare variations and 4 copy number variations. We have also further extended our cohort to 2,029 cases and 1,896 controls with the exclusion of individuals certain of having had HBV vaccine. We aim to identify more novel less frequent/rare variations and copy number variations associated with CHB. With the already proven strategies and techniques, also the experience obtained from the phase　I　study we anticipate that this phase of the project will yield good results, which will shed light on pathogenesis of CHB，and may have potential in medical practice.