Laing I A, Goldblatt J, Eber E, Hayden C M, Rye P J, Gibson N A, Palmer L J, Burton P R, Le Souëf P N
Department of Paediatrics, University of Western Australia, Children's Hospital Medical Centre, Perth.
J Med Genet. 1998 Jun;35(6):463-7. doi: 10.1136/jmg.35.6.463.
Several quantitative traits associated with the asthma phenotype have been linked to markers on chromosome 11q13, although the gene responsible has yet to be well established. The gene for Clara cell secretory protein (CC16) is an ideal candidate for involvement in an inherited predisposition to asthma because of its chromosomal location, the role of the CC16 protein in controlling airway inflammation, and differences in levels of the protein between asthmatics and healthy controls. All three CC16 exons were screened in an unselected population of 266 subjects from 76 families and a cohort of 52 severely asthmatic children. A combination of single strand conformational polymorphism (SSCP) analysis, heteroduplex analysis, DNA sequencing, and restriction digestion was used. Mutation detection methods identified an adenine to guanine substitution in the CC16 gene at position 38 (A38G) downstream from the transcription initiation site within the non-coding region of exon 1. In the unselected population, 43.6% were homozygous for the polymorphic sequence (38GG) and 46.2% were heterozygous (38AG). All the asthmatic and unaffected children from both populations were selected for an unmatched case control analysis consisting of 67 asthmatic and 46 unaffected subjects. Those homozygous for the published sequence (38AA) had a 6.9-fold increased risk of developing asthma (p=0.049) and heterozygotes (38AG) a 4.2-fold increased risk (p=0.028). Modelling of genotype as a continuous covariate indicated evidence of a significant linear trend across the three genotypes (odds ratio=2.84 per unit increase in genotype code, p=0.018). These associations were independent of age, gender, and tobacco smoke exposure. These data and the known anti-inflammatory role of CC16 in the respiratory tract suggest that alteration to the gene at position 38 may contribute to asthma.
尽管尚未明确负责的基因，但一些与哮喘表型相关的数量性状已与11号染色体q13上的标记物相关联。由于其染色体定位、CC16蛋白在控制气道炎症中的作用以及哮喘患者与健康对照者之间该蛋白水平的差异， Clara细胞分泌蛋白（CC16）基因是参与哮喘遗传易感性的理想候选基因。对来自76个家庭的266名未经过筛选的受试者以及52名重度哮喘儿童队列中的所有三个CC16外显子进行了筛查。使用了单链构象多态性（SSCP）分析、异源双链分析、DNA测序和限制性酶切消化相结合的方法。突变检测方法在第1外显子非编码区转录起始位点下游38位（A38G）处的CC16基因中鉴定出腺嘌呤到鸟嘌呤的替换。在未经过筛选的人群中，43.6%为多态性序列纯合子（38GG），46.2%为杂合子（38AG）。从这两个人群中选取了所有哮喘儿童和未患病儿童进行非匹配病例对照分析，其中包括67名哮喘患者和46名未患病受试者。那些已发表序列的纯合子（38AA）患哮喘的风险增加了6.9倍（p = 0.049），杂合子（38AG）患哮喘的风险增加了4.2倍（p = 0.028）。将基因型作为连续协变量进行建模表明，在三种基因型之间存在显著线性趋势的证据（基因型编码每增加一个单位，优势比 = 2.84，p = 0.018）。这些关联独立于年龄、性别和烟草烟雾暴露。这些数据以及CC16在呼吸道中已知的抗炎作用表明，38位基因的改变可能导致哮喘。
