全外显子组IgA肾病低频及罕见遗传变异研究

IgA肾病(IgAN）是影响我国人口健康的常见病，现有的全基因组相关关系研究只研究等位基因频率≥5%的常见遗传变异，还未有任何对低频或罕见遗传变异（等位基因频率<5%）的报导。新一代测序技术为在全外显子组范围内挖掘疾病相关的低频及罕见遗传变异提供了新的契机，有快捷地捕获功能意义明确，有强疾病效应的遗传变异的优势。IgA肾病的遗传学基础是本课题组长期研究方向之一。我们前期已获得了3个这一方向的国家自然科学基金。我们已完成了对10个IgAN家庭中的先证者及每家庭一个正常成员的全外显子组测序，筛选到了5个低频/罕见遗传变异，全为未报道过的新基因内的新变异。我们还收集了910例IgAN病人、1057正常对照及347个parents-patient家庭。现申请经费对这些候选基因进行病例-对照及以家庭为基础的相关关系研究，并对证实相关的遗传变异进行功能学分析，以期对IgA肾病的发病机理进行进一步研究。

IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide. The current genome-wide association studies only studied genetic variations with frequencies ≥ 0.05. The role of low frequency and rare alleles (minor allele frequence< 0.05) in IgA nephropathy remains lacking. The emerging technology of next generation sequencing has provided new opportunities for low frequency and rare disease allele discovery. It has the advantages of directly unravel alleles with strong phenotypic effects and causative to conditions under study. Genetic background of IgA nephropathy is one of the long term research directions of my research team. We have performed exome sequencing in the index cases and one unaffected members in each of the 10 IgA nephropathy families and have selected 5 low frequency/rare candidate alleles. We have also assembled the precious IgA nephropathy resources comprising 910 biopsy-proven IgA nephropathy patients, 1057 matched controls and 347 parents-patient trios during last 10 years. We propose to further study these and newly selected low frequency and rare alleles by a case-control and family-based studies. The associated alleles will also be analyzed by functional tests. We anticipate that the outcomes of the proposed study will shed more light on the mechanisms of IgA nephropathy and may have potentials in translational medicine.