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。该疾病具有广泛的临床病程，从自发缓解到致残器官损伤甚至死亡。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）中的基因相关。在一项全基因组连锁研究中，我们发现了7个与病因学相关的染色体区域，最近将BTNL 2鉴定为6号染色体上的一个新的结节病基因。在一项使用100K Affytron微阵列的全基因组关联研究中，我们发现了7号和10号染色体上的两个额外的易感区域。在本项目中，将从5570例流行病例中提取2000例结节病患者，并对MHC基因、BTNL 2和来自我们全基因组500K SNP芯片研究和正在进行的复制的估计15个新位置候选基因进行基因分型。将根据标准化方案在31个研究中心对患者进行表型分析，并评估其表型与基因型之间的关系。特别是，将具有罕见、不利和慢性疾病病程（包括心脏、神经、皮肤和耐药表现）的患者的基因型与自发消退相关的基因型进行比较。患者队列将足够大，以包含足够大量的罕见表型，从而确保相应结果的预后有用性。在实践中，不良基因型患者应密切监测，并将受益于新的治疗方法。

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.