Carter K W, Pluzhnikov A, Timms A E, Miceli-Richard C, Bourgain C, Wordsworth B P, Jean-Pierre H, Cox N J, Palmer L J, Breban M, Reveille J D, Brown M A
Laboratory for Genetic Epidemiology, Western Australian Institute for Medical Research, UWA Centre for Medical Research, University of Western Australia, Nedlands, Western Australia 6009, Australia.
Rheumatology (Oxford). 2007 May;46(5):763-71. doi: 10.1093/rheumatology/kel443. Epub 2007 Jan 27.
Ankylosing spondylitis (AS) is a debilitating chronic inflammatory condition with a high degree of familiality (lambda(s) = 82) and heritability (>90%) that primarily affects spinal and sacroiliac joints. Whole genome scans for linkage to AS phenotypes have been conducted, although results have been inconsistent between studies and all have had modest sample sizes. One potential solution to these issues is to combine data from multiple studies in a retrospective meta-analysis.
The International Genetics of Ankylosing Spondylitis Consortium combined data from three whole genome linkage scans for AS (n = 3744 subjects) to determine chromosomal markers that show evidence of linkage with disease. Linkage markers typed in different centres were integrated into a consensus map to facilitate effective data pooling. We performed a weighted meta-analysis to combine the linkage results, and compared them with the three individual scans and a combined pooled scan.
In addition to the expected region surrounding the HLA-B27 gene on chromosome 6, we determined that several marker regions showed significant evidence of linkage with disease status. Regions on chromosome 10q and 16q achieved 'suggestive' evidence of linkage, and regions on chromosomes 1q, 3q, 5q, 6q, 9q, 17q and 19q showed at least nominal linkage in two or more scans and in the weighted meta-analysis. Regions previously associated with AS on chromosome 2q (the IL-1 gene cluster) and 22q (CYP2D6) exhibited nominal linkage in the meta-analysis, providing further statistical support for their involvement in susceptibility to AS.
These findings provide a useful guide for future studies aiming to identify the genes involved in this highly heritable condition.
强直性脊柱炎（AS）是一种使人衰弱的慢性炎症性疾病，具有高度家族聚集性（λs = 82）和遗传性（> 90%），主要影响脊柱和骶髂关节。尽管研究结果不一致且样本量均较小，但已对与AS表型相关的全基因组进行了扫描。解决这些问题的一个潜在办法是在回顾性荟萃分析中合并多项研究的数据。
国际强直性脊柱炎遗传学联盟合并了三项针对AS的全基因组连锁扫描数据（n = 3744名受试者），以确定显示与疾病存在连锁证据的染色体标记。将在不同中心分型的连锁标记整合到一个一致性图谱中，以促进有效的数据汇总。我们进行了加权荟萃分析以合并连锁结果，并将其与三项单独扫描以及合并后的汇总扫描结果进行比较。
除了6号染色体上HLA - B27基因周围的预期区域外，我们还确定了几个标记区域显示出与疾病状态存在显著的连锁证据。10q和16q染色体区域获得了“提示性”连锁证据，1q、3q、5q、6q、9q、17q和19q染色体区域在两项或更多扫描以及加权荟萃分析中显示出至少名义上的连锁。先前与AS相关的2q染色体（IL - 1基因簇）和22q染色体（CYP2D6）区域在荟萃分析中表现出名义上的连锁，为它们参与AS易感性提供了进一步的统计学支持。
这些发现为未来旨在鉴定参与这种高度遗传性疾病的基因的研究提供了有用的指导。
