Raby Benjamin A, Silverman Edwin K, Lazarus Ross, Lange Christoph, Kwiatkowski David J, Weiss Scott T
Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Hum Mol Genet. 2003 Aug 15;12(16):1973-9. doi: 10.1093/hmg/ddg208.
Chromosome 12q13-24 is among the regions most frequently identified in genome-wide surveys for asthma susceptibility loci, with reports of two distinct clusters of positive linkage signals: one near the interferon gamma locus, the other near the nitric oxide synthase 1 locus. These results suggest that 12q harbors several asthma susceptibility loci. We evaluated this possibility in a subset of families ascertained through the Childhood Asthma Management Program (CAMP) Genetics Ancillary Study. Fifty-five nuclear families with at least two asthmatic siblings (212 individuals) were genotyped using 32 microsatellite markers. Non-parametric linkage analysis was performed for the asthma phenotype (qualitative). Multipoint variance component-based linkage analysis was performed for five quantitative asthma-related traits: (i) percent predicted forced expiratory volume in one second (FEV(1)); (ii) dose of methacholine resulting in 20% fall in FEV(1) from baseline (PC(20)); (iii) post-bronchodilator percent change in FEV(1) (BDPR); (iv) serum eosinophil levels (EOS); and (v) total serum IgE levels (IgE). Three separate and distinct loci demonstrated evidence suggestive of linkage: asthma at 68 cM (exact P-value=0.05), airways responsiveness (PC(20)) at 147 cM (P=0.01), and indices of pulmonary function (FEV1, BDPR) at 134 cM (P=0.05 and P<0.01, respectively). No linkage was observed for the atopy-related phenotypes. We provide further evidence supporting the presence of an asthma susceptibility locus at the proximal end of chromosome 12q, as well as new evidence for additional loci more distally that account for unique features of the asthma phenotype. Fine mapping efforts for these loci are warranted.
在全基因组哮喘易感基因座调查中，12号染色体的12q13 - 24区域是最常被识别出的区域之一，有报告称存在两个不同的阳性连锁信号簇：一个靠近干扰素γ基因座，另一个靠近一氧化氮合酶1基因座。这些结果表明12q含有多个哮喘易感基因座。我们在通过儿童哮喘管理项目（CAMP）遗传学辅助研究确定的一部分家庭中评估了这种可能性。使用32个微卫星标记对55个至少有两个哮喘患儿同胞的核心家庭（212名个体）进行了基因分型。对哮喘表型（定性）进行了非参数连锁分析。对五个与哮喘相关的定量性状进行了基于多点方差成分的连锁分析：（i）一秒用力呼气量占预计值百分比（FEV(1)）；（ii）导致FEV(1)从基线下降20%的乙酰甲胆碱剂量（PC(20)）；（iii）支气管扩张剂后FEV(1)的百分比变化（BDPR）；（iv）血清嗜酸性粒细胞水平（EOS）；以及（v）总血清IgE水平（IgE）。三个独立且不同的基因座显示出连锁的证据：68厘摩处的哮喘（确切P值 = 0.05）、147厘摩处的气道反应性（PC(20)）（P = 0.01）以及134厘摩处的肺功能指标（FEV1、BDPR）（分别为P = 0.05和P < 0.01）。未观察到与特应性相关表型的连锁。我们提供了进一步的证据支持12q近端存在哮喘易感基因座，以及更多远端其他基因座的新证据，这些基因座解释了哮喘表型的独特特征。对这些基因座进行精细定位的工作是有必要的。
