Bache Iben, Nielsen Nete M, Rostgaard Klaus, Tommerup Niels, Frisch Morten
Wilhelm Johannsen Centre for Functional Genome Research, University of Copenhagen, Copenhagen, Denmark.
Arthritis Rheum. 2007 Jul;56(7):2402-9. doi: 10.1002/art.22652.
Constitutional structural chromosomal rearrangements (CSCRs) have facilitated the identification of genes associated with early-onset monogenic disorders and, more recently, genes associated with common and late-onset disorders. In an attempt to find genetic clues to their etiologies, we studied the risk of autoimmune diseases in a Danish cohort of CSCR carriers.
We followed up 4,866 CSCR carriers over 71,230 person-years (1980 through 2004) for autoimmune diseases recorded in the Danish Hospital Discharge Register. Standardized incidence ratios (SIRs) and 95% confidence intervals (95% CIs) served as measures of the relative risk. To identify possible candidate loci for autoimmune diseases, the reported chromosomal breakpoints and deletions in CSCR carriers who developed autoimmune diseases were compared with previously suggested loci for these diseases.
The overall risk of any autoimmune disease among CSCR carriers was inconspicuous (SIR 1.2 [95% CI 0.95-1.5]; n = 74 cases observed versus 61.3 expected), but carriers of rearrangements involving chromosomes 2, 19, and 21 were at significantly increased risk. For the specific autoimmune diseases studied, cohort members were at significantly increased risk of Dupuytren's contracture, pernicious anemia, and juvenile rheumatoid arthritis (JRA). Sixteen carriers who developed an autoimmune disease had a chromosomal breakpoint or deletion coinciding with a previously suggested locus, including deletions 18p11, 18q22, and 22q11 associated with JRA.
CSCR carriers do not have a generalized predisposition to autoimmune diseases. However, we confirmed a number of reported susceptibility loci for JRA, and we suggest new susceptibility loci on chromosomes 5 and 11 for Dupuytren's contracture, and 19p13 as a possible shared susceptibility locus for a range of autoimmune diseases.
染色体结构组成重排（CSCRs）有助于识别与早发性单基因疾病相关的基因，以及最近与常见和迟发性疾病相关的基因。为了寻找其病因的遗传线索，我们在丹麦一个CSCR携带者队列中研究了自身免疫性疾病的风险。
我们对4866名CSCR携带者进行了71230人年（1980年至2004年）的随访，以获取丹麦医院出院登记册中记录的自身免疫性疾病信息。标准化发病率比（SIRs）和95%置信区间（95% CIs）作为相对风险的衡量指标。为了确定自身免疫性疾病可能的候选基因座，将发生自身免疫性疾病的CSCR携带者中报告的染色体断点和缺失与这些疾病先前提出的基因座进行了比较。
CSCR携带者中任何自身免疫性疾病的总体风险不明显（SIR 1.2 [95% CI 0.95 - 1.5]；观察到74例，预期61.3例），但涉及染色体2、19和21的重排携带者风险显著增加。对于所研究的特定自身免疫性疾病，队列成员患掌腱膜挛缩症、恶性贫血和青少年类风湿性关节炎（JRA）的风险显著增加。16名发生自身免疫性疾病的携带者有一个染色体断点或缺失与先前提出的基因座重合，包括与JRA相关的18p11、18q22和22q11缺失。
CSCR携带者对自身免疫性疾病没有普遍的易感性。然而，我们证实了一些报告的JRA易感基因座，并且我们提出染色体5和11上有新的掌腱膜挛缩症易感基因座，以及19p13作为一系列自身免疫性疾病可能的共同易感基因座。
