Role of inducible nitric oxide synthase in asthma risk and lung function growth during adolescence
Role of inducible nitric oxide synthase in asthma risk and lung function growth during adolescence
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DOI：
10.1136/thx.2009.114355
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发表时间：
2010-02-01
期刊：
影响因子：
10
通讯作者：
Gilliland, Frank D.
中科院分区：
文献类型：
--
作者：
Islam, Talat;Breton, Carrie;Gilliland, Frank D.
背景诱导型一氧化氮合酶（Inducible nitric oxide synthase，iNOS）由NOS 2A编码，在环境刺激下产生NO，导致亚硝化应激。由于亚硝化应激影响呼吸系统的健康，有人假设，NOS 2A的变异与哮喘的发病率和肺功能的增长在adolescence.Methods在这项前瞻性研究中，肺功能测定在学校和哮喘的存在或不存在，每年通过问卷调查，儿童参加南加州儿童健康研究。24个单核苷酸多态性（SNPs）的NOS 2A区域（与7个启动子SNPs在一个单倍型块），跨越20 kb上游和10 kb下游进行基因分型。NOS 2A区域与哮喘或肺功能生长之间的关联使用遗传块特异性主成分和单倍型分析进行了测试。本研究仅对1596例拉美裔和2108例白人儿童进行哮喘和肺功能发育分析。结果在启动子区发现一对“阴阳”单倍型与新发哮喘和肺功能发育密切相关。阴单倍型（h 0111101）与44%的哮喘风险增加相关（p=0.003）和10 - 18岁1秒用力呼气量（FEV 1）增长减少（-29.46ml，p=0.07），而“阳”（h1000010）单倍型与哮喘风险降低23%（p=0.13）和更好的FEV 1增长（43.84ml，p=0.01）相关。结论NOS 2A基因启动子区常见单倍型与新发哮喘和肺功能发育有关。这些影响在GSTM 1“null”基因型的青少年中更强。
Background Inducible nitric oxide (NO) synthase (iNOS, encoded by NOS2A) produces NO in response to environmental stimuli, which can result in nitrosative stress. Because nitrosative stress affects respiratory health, it was hypothesised that variants in NOS2A are associated with asthma incidence and lung function growth during adolescence.Methods In this prospective study, spirometric testing was performed at school and a presence or absence of asthma was ascertained annually by questionnaire among children participating in the Southern California Children's Health Study. 24 single nucleotide polymorphisms (SNPs) of the NOS2A region (with seven promoter SNPs in one haplotype block), spanning 20 kb upstream and 10 kb downstream were genotyped. Association between the NOS2A region and asthma or lung function growth was tested using genetic block-specific principal component and haplotype analyses. This study was restricted to children with Latino and Caucasian ancestry for analyses of both asthma (n=1596) and lung function growth (n=2108).Result A pair of "yin-yang" haplotypes in the promoter region showed strong association with new-onset asthma and lung function growth. The "yin" haplotype (h0111101) was associated with 44% increased asthma risk (p=0.003) and reduced forced expiratory volume in 1 s (FEV1) growth from 10 to 18 years of age (-29.46 ml, p=0.07), whereas the "yang"(h1000010) haplotype was associated with 23% reduced asthma risk (p=0.13) and better FEV1 growth (43.84 ml, p=0.01). Furthermore, the increased asthma risk associated with h0111101 was restricted to children with the GSTM1 "null" genotype (interaction p=0.002, HR 1.89, 95% CI 1.34 to 2.60).Conclusion Common haplotypes in the NOS2A promoter are associated with new-onset asthma and lung function growth. These effects are stronger in adolescents with the GSTM1 "null" genotype.