Ober C, Tsalenko A, Parry R, Cox N J
Department of Human Genetics, The University of Chicago, Chicago, IL, 60637, USA.
Am J Hum Genet. 2000 Nov;67(5):1154-62. doi: 10.1016/S0002-9297(07)62946-2. Epub 2000 Oct 5.
A genomewide screen for asthma- and atopy-susceptibility loci was conducted, using 563 markers, in 693 Hutterites who are members of a single 15-generation pedigree, nearly doubling the sample size from the authors' earlier studies. The resulting increase in power led to the identification of 23 loci in 18 chromosomal regions showing evidence for linkage that is, in general, 10-fold more significant (P<.001 vs. P<.01) than the linkages reported previously in this population. Moreover, linkages to loci in 11 chromosomal regions were identified for the first time in the Hutterites in this report, including five regions (5p, 5q, 8p, 14q, and 16q) showing evidence both of linkage, by the likelihood ratio (LR) chi(2), and of disequilibrium, by the transmission/disequilibrium test. A region on chromosome 19 continues to show evidence for linkage, by both tests, in this study. Studies of 17 candidate genes provide evidence for association with variation in the IL4RA gene (16p12), the HLA class II genes (6p21), and the interferon-alpha gene cluster (9p22), but the lack of evidence for linkage in these regions by the LR chi(2) test suggests that these are minor susceptibility loci. A polymorphism in the CD14 gene is in linkage disequilibrium with an as yet unidentified susceptibility allele in the 5q cytokine cluster, a region showing evidence for linkage among the Hutterites. Finally, 10 of the regions showing evidence for linkage in the Hutterites have shown evidence of linkage to related phenotypes in other genome screens, suggesting that these regions may contain common alleles that have relatively large effects on asthma and atopy phenotypes in diverse populations.
利用563个标记，对一个包含15代人的单一家系中的693名哈特派信徒进行了全基因组哮喘和特应性易感性位点筛查，样本量几乎是作者早期研究的两倍。由此带来的检验效能增加使得在18个染色体区域中鉴定出23个位点，显示出连锁证据，总体而言，这些连锁比该人群先前报道的连锁显著10倍（P<0.001对P<0.01）。此外，本报告首次在哈特派信徒中鉴定出与11个染色体区域位点的连锁，包括5个区域（5p、5q、8p、14q和16q），通过似然比（LR）卡方检验显示出连锁证据，通过传递/不平衡检验显示出不平衡证据。在本研究中，19号染色体上的一个区域通过两种检验均继续显示出连锁证据。对17个候选基因的研究提供了与IL4RA基因（16p12）、HLA II类基因（6p21）和干扰素-α基因簇（9p22）变异相关的证据，但LR卡方检验在这些区域缺乏连锁证据，表明这些是次要的易感位点。CD14基因中的一个多态性与5q细胞因子簇中一个尚未鉴定的易感等位基因处于连锁不平衡状态，该区域在哈特派信徒中显示出连锁证据。最后，在哈特派信徒中显示出连锁证据的10个区域在其他基因组筛查中也显示出与相关表型的连锁证据，这表明这些区域可能包含对不同人群的哮喘和特应性表型有相对较大影响的常见等位基因。
