FAMILY STUDIES OF THE GENETICS OF ANKYLOSING SPONDYLITIS

虽然人类白细胞抗原B27被认为是强直性脊柱炎(AS)发生发展的基本特征，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AS的发病机制。整个MHC的贡献只有31%。对来自英国的同胞对的连锁分析表明，包括MHC在内的8个染色体区域有中度连锁的证据。然而，许多基因都包含在这些区域中，这些区域中哪些是实际的疾病易感基因尚未确定。因此，这项建议的具体目标是：1)建立一个最近有AS临床或基因研究记录的研究人员联盟(因此建立了患者队列)，总部设在北美的10个学术医疗中心(北美脊柱炎协会-NASC)，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AS纽约标准的家庭；2)从美国脊柱炎协会(SAA)的成员中，确定受类似影响的家庭，并通过问卷、病历回顾和骨盆X光检查来核实两组中的诊断；3)从受影响和未受影响的同胞对及其父母(如有的话)采集50毫升血液，以建立这400个家庭的血清、基因组DNA和冰冻淋巴细胞库；4)通过对人类白细胞抗原-B27等位基因、B60和人类白细胞抗原DRB1、DQA1和DQB1等位基因的DNA分型，确定MHC对AS易感性的贡献；5)在400个高加索家庭中，使用紧密分布的微卫星标记，对符合和不一致的同胞对AS进行全基因组搜索；6)使用多点分析对非MHC基因进行微卫星分析，以利用传递不平衡检验(TDT)对与AS有关的基因进行精细定位研究；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相关疾病相关基因的突变。

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.