FAMILY STUDIES OF THE GENETICS OF ANKYLOSING SPONDYLITIS

尽管HLA-B27被认为是强直性脊柱炎（AS）发展的一个基本特征，但最近的研究表明，主要组织相容性复合体（MHC）内外的其他基因和染色体区域也参与了该疾病的发病机制。 整个MHC的贡献仅为31%。 来自英国的同胞对的连锁分析显示，包括MHC在内的8个染色体区域与AS有中度连锁证据。 然而，许多基因包含在这些区域中，并且这些区域中的哪些是实际的疾病易感基因尚未确定。 因此，本提案的具体目标是：1）建立一个具有AS临床或遗传学研究近期记录的研究者联盟（因此建立了患者队列），基于北美10个学术医疗中心（北美脊柱炎协会-NASC），以便从其队列中识别出至少有两个兄弟姐妹符合AS的改良纽约标准的家庭; 2）从美国脊柱炎协会（SAA）的成员中，通过问卷调查、病历回顾和骨盆X线片，确定两组中有相似患病的家庭，并验证诊断; 3）从患病和未患病的同胞对以及在可用时从其双亲收集50 ml血液，以建立血清库，（4）通过对HLA-B27、B60和HLA-DRB 1、DQA 1和DQB 1等位基因的DNA分型，分析MHC在AS易感性中的作用; 5）在400个高加索人家庭中，使用紧密间隔的微卫星标记在一致和不一致的同胞对中进行AS的全基因组搜索; 6）利用多点分析技术对非MHC基因进行微卫星多态性分析，利用传递不平衡检验（TDT）对AS相关基因进行精细定位研究; 7）研究25例AS患者和25例正常对照的3 ~ 4个候选基因的序列变异，以确定与AS相关的突变和疾病相关的多态性。

Although HLA-B27 is regarded as an essential feature for the development of ankylosing spondylitis (AS, recent studies have implicated other genes and chromosomal regions, both inside and outside the major histocompatibility complex (MHC), in the pathogenesis of the disorder. The entire MHC contribution has been calculated at only 31 percent. Linkage analysis of sib pairs from the United Kingdom has shown eight chromosomal regions, including the MHC, to have moderate evidence of linkage to AS. However, many genes are contained in these regions, and which are the actual disease susceptibility genes within these regions has not been established. Thus, the specific aims of this proposal are: 1) to establish a consortium of investigators with a recent record of clinical or genetic research in AS (and hence established patient cohorts) based at 10 academic medical centers throughout North America (the North American Spondylitis Consortium-NASC) in order to identify from their cohorts families with at least two siblings fulfilling the modified New York criteria for AS; 2) from the membership of the Spondylitis Association of America (SAA), to identify similarly affected families and verify the diagnoses in both groups by questionnaire, medical record review and pelvic radiographs; 3) to collect 50 ml of blood from affected and unaffected sib pairs and, when available, both their parents in order to establish a bank of sera, genomic DNA and frozen lymphocytes from these 400 families; 4) to characterize the MHC contribution to predisposition to AS by DNA typing for HLA-B27 alleles, B60 and HLA-DRB1, DQA1 and DQB1 alleles; 5) to conduct a genome wide search using closely spaced microsatellite markers in sib pairs concordant and discordant for AS in the 400 Caucasian families; 6) to conduct microsatellite polymorphism analyses of non-MHC genes using multipoint analyses for fine mapping studies of genes linked to AS using transmission disequilibrium testing (TDT); and finally, 7) to study sequence variation of three to four candidate genes in 25 AS patients and 25 controls to identify the mutations an disease-relevant polymorphisms involved in AS.