FAMILY STUDIES OF THE GENETICS OF ANKYLOSING SPONDYLITIS

尽管HLA-B27被认为是强直性脊柱炎（as）发病的重要特征，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的贡献仅占31%。对来自英国的兄弟姐妹对的连锁分析显示，包括MHC在内的八个染色体区域与AS有一定的连锁关系。然而，在这些区域中包含了许多基因，而哪些是这些区域中真正的疾病易感基因尚未确定。因此，本提案的具体目的是：1)在北美10个学术医疗中心（北美脊柱炎联盟- nasc）建立一个具有近期AS临床或遗传研究记录的研究人员联盟（从而建立患者队列），以便从他们的队列中确定至少有两个兄弟姐妹符合修改后的纽约AS标准的家庭；2)来自美国脊柱炎协会（SAA）的会员，以确定类似的影响家庭，并通过问卷调查，医疗记录审查和骨盆x线片验证两组的诊断；3)从受感染和未受感染的兄弟姐妹身上采集50毫升血液，并在可能的情况下从他们的父母身上采集50毫升血液，以便建立这400个家庭的血清、基因组DNA和冷冻淋巴细胞库；4)通过HLA-B27、B60、HLA-DRB1、DQA1和DQB1等位基因的DNA分型，研究MHC对AS易感性的贡献；5)利用紧密间隔的微卫星标记，对400个高加索人AS家族的一致性和非一致性兄弟姐妹进行全基因组搜索；6)利用多点分析对非mhc基因进行微卫星多态性分析，利用传递不平衡测试（TDT）对AS相关基因进行精细定位研究；最后，7)研究25例AS患者和25例对照中3 - 4个候选基因的序列变异，以确定AS中涉及的突变和疾病相关多态性。

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.