Genotype-Phenotype Relationship in Sarcoidosis

结节病是一种病因不明的全身性肉芽肿性疾病，主要累及肺部。这种疾病有广泛的临床病程，从自发缓解到致残器官损害甚至死亡。有越来越多的证据表明结节病的遗传易感性，包括与主要组织相容性复合体(MHC)中的基因有关。在全基因组连锁研究中，我们识别了7个与病原学相关的染色体区域，最近在6号染色体上发现了一个新的结节病基因BTNL2。在使用100K Affymetrix微阵列进行的全基因组关联研究中，我们在第7和10号染色体上发现了另外两个易感区域。在本项目中，将从5570例流行病例中提取2000名结节病患者，并对MHC基因BTNL2进行基因分型，以及从我们的全基因组500K SNP芯片研究和正在进行的复制中估计15个新的位置候选基因。根据标准化方案，患者将在31个研究地点进行表型鉴定，并将评估他们的表型和基因之间的关系。特别是，具有罕见、不利和慢性病病程的患者的基因类型，包括心脏、神经、皮肤和治疗抵抗的表现，将与那些与自发解决有关的患者进行比较。患者队列将足够大，以包含足够多的罕见表型，以确保各自结果的预后有用性。在实践中，应密切监测基因不良的患者，并将从新的治疗方法中受益最大。

Sarcoidosis is a systemic granulomatous disorder of unknown aetiology, preferentially affecting the lung. The disease has a wide spectrum of clinical courses, ranging from spontaneous remission to disabling organ damage or even death. There is accumulating evidence for a genetic susceptibility to sarcoidosis, including an association with genes in the major histocompatibility complex (MHC). In a genome-wide linkage study, we recognized seven chromosomal regions of aetiological relevance and recently identified BTNL2 as a new sarcoidosis disease gene on chromosome 6. In a genome-wide association study using 100K Affymetrix micro-arrays, we uncovered two additional susceptibility regions on chromosomes 7 and 10. In the present project, 2000 sarcoidosis patients will be extracted from a cohort of 5570 prevalent cases and genotyped for MHC genes, BTNL2, and an estimated 15 new positional candidate genes from our genome-wide 500K SNP chip studies and ongoing replication. Patients will be phenotyped at 31 study sites according to a standardized protocol and the relationship between their phenotype and genotype will be assessed. In particular, genotypes of patients with rare, unfavourable and chronic disease courses, including cardiac, neurological, cutaneous, and therapy-resistant manifestations, will be compared to those associated with spontaneous resolution. The patient cohort will be large enough to contain a sufficiently large number of rare phenotypes so as to ensure prognostic usefulness of the respective results. In practise, patients with adverse genotypes should be intensely monitored and would benefit most from new therapeutic approaches.