17号染色体长臂2区1带（17q21）变异与被动吸烟对早发性哮喘的影响
2009/03/09
背景：全基因组关联研究显示17号染色体长臂2区1带（17q21）染色体的变异与哮喘发生危险度的增加有一定的相关性。为此，我们以家庭为单位收集了一个大样本资料，其中包括了外在表型与环境因素等数据，它们来自哮喘遗传与环境的流行病学研究。
方法：我们对372个哮喘家庭共1511个个体进行哮喘关联分析，观察其17q21中36个单核苷酸多态性(SNPs)。同时，根据其哮喘发病年龄、是否早年暴露于烟草环境进行了遗传异质性的观察。
结果：17个SNPs与哮喘显著相关，其中三个(rs8069176, rs2305480, he rs4795400)密切相关(P<0.001)。根据有序子集回归分析原则，定义4岁或4岁前发现有哮喘发作者为早发性哮喘。四个SNPs与早发性哮喘密切相关 (P<10-5)，不存在与迟发性哮喘相关的SNPs。在早年被动吸烟患者中，六个SNPs与早发性哮喘密切相关(P<5 x 10-5)。根据最佳拟合隐性模型，在被动吸烟人群中，相对于AG和AA，基因型为纯合子(GG)的SNP拥有与哮喘最强的相关性，传递风险系数增高2.9 (P=2.8 x 10-6； 在烟草暴露与非烟草暴露组之间，SNP与哮喘早期发病相关性差异的P值为0.006)
结论：本研究表明，17q21基因变异会增加早发性哮喘的危险，此危险又因早年被动吸烟而增高。该发现有助于更好地了解17q21变异在哮喘的病理生理当中的功能地位。.
（张清玲 深圳市第二人民医院呼吸内科 518039 摘译）
( N Engl J Med ,2008 Nov;359:1985-1994.)
Emmanuelle Bouzigon, M.D., Ph.D., Eve Corda, M.S., Hugues Aschard, M.S., et al.Effect of 17q21 Variants and Smoking Exposure in Early-Onset Asthma.
N Engl J Med ,2008 Nov;359:1985-94.
N Engl J Med ,2008 Nov;359:1985-94.
Background
A genomewide association study has shown an association between variants at chromosome
17q21 and an increased risk of asthma.To elucidate the relationship between this locus and disease,we examined a large, family-based data set thatincluded
extensive phenotypic and environmental data from the Epidemiological Study
on the Genetics and Environment of Asthma.
Methods
We tested 36 single-nucleotide polymorphisms (SNPs) in the 17q21 region in 1511 subjects
from 372 families for an association with asthma.We also tested for genetic
heterogeneity according to the age at the onset of asthma and exposure to environmental
tobacco smoke in early life.
Results
Eleven SNPs were significantly associated with asthma (P<0.01), of which three
(rs8069176, rs2305480, and rs4795400) were strongly associated (P<0.001). Orderedsubset
regression analysis led us to select an onset at 4 years of age or younger to
classify patients as having early-onset asthma. Association with early-onset asthma
was highly significant (P<10−5 for four SNPs), whereas no association was found with
late-onset asthma. With respect to exposure to environmental tobacco smoke in
early life, we observed a significant association with early-onset asthma only in exposed
subjects (P<5×10−5 for six SNPs). Under the best-fitting recessive model, homozygous
status (GG) at the most strongly associated SNP (rs8069176) conferred an
increase in risk by a factor of 2.9, as compared with other genotypes (AG and AA)
in the group exposed to environmental tobacco smoke (P = 2.8×10−6; P = 0.006 for
the test for heterogeneity of the SNP effect on early-onset asthma between groups
with tobacco exposure and those without such exposure).
Conclusions
This study shows that the increased risk of asthma conferred by 17q21 genetic variants
is restricted to early-onset asthma and that the risk is further increased by
early-life exposure to environmental tobacco smoke. These findings provide a greater
understanding of the functional role of the 17q21 variants in the pathophysiology
of asthma.
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