Chromosome 17: association of a large inversion polymorphism with corticosteroid response in asthma.
Chromosome 17: association of a large inversion polymorphism with corticosteroid response in asthma.
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DOI：
10.1097/fpc.0b013e3282fe6ebf
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发表时间：
2008-08
影响因子：
2.6
通讯作者：
Weiss ST
中科院分区：
文献类型：
--
作者：
Tantisira KG;Lazarus R;Litonjua AA;Klanderman B;Weiss ST
CRHR1位于17号染色体上一大片保守的连锁不平衡(LD)区域，位于该区域内，与吸入性皮质类固醇激素反应有关。我们假设CRHR1变异体与倒位有关，支持自然选择在对皮质类固醇的遗传反应中的潜在作用。我们检测了6个跨越Chr17：40,410,565-42,372,240的单核苷酸多态(SNPs)，其中4个SNPs定义了倒位状态。在CRHR1基因倒位和先前与吸入皮质类固醇的肺功能反应相关的CRHR1 SNP之间发现了相似的等位基因频率和较强的LD。在成人哮喘患者中，每个反转定义的单核苷酸多态与吸入糖皮质激素反应密切相关(p值0.002-0.005)。因此，CRHR1对吸入皮质类固醇的反应可以通过倒位状态的自然选择或与另一基因的远程LD来解释。有必要对染色体多样性区域进行额外的药物遗传学研究，包括拷贝数变异和倒置。
A 900-KB inversion exists within a large region of conserved linkage disequilibrium (LD) on chromosome 17. CRHR1 is located within the inversion region and associated with inhaled corticosteroid response in asthma. We hypothesized that CRHR1 variants are in LD with the inversion, supporting a potential role for natural selection in the genetic response to corticosteroids. We genotyped 6 single nucleotide polymorphisms (SNPs) spanning chr17:40,410,565–42,372,240, including 4 SNPs defining inversion status. Similar allele frequencies and strong LD were noted between the inversion and a CRHR1 SNP previously associated with lung function response to inhaled corticosteroids. Each inversion-defining SNP was strongly associated with inhaled corticosteroid response in adult asthma (p-values 0.002–0.005). The CRHR1 response to inhaled corticosteroids may thus be explained by natural selection resulting from inversion status or by long-range LD with another gene. Additional pharmacogenetic investigations into to regions of chromosomal diversity, including copy number variation and inversions, are warranted.