TMEM196 多态性与哮喘中 NSAID 加重的呼吸道疾病的关联。
Associations between TMEM196 polymorphisms and NSAID-exacerbated respiratory disease in asthma.
机构信息
Department of Medical Bioscience, Graduate School, Soonchunhyang University, Asan.
Department of Internal Medicine, Division of Allergy and Respiratory Medicine, Soonchunhyang University Bucheon Hospital, Bucheon.
出版信息
Pharmacogenet Genomics. 2019 Jun;29(4):69-75. doi: 10.1097/FPC.0000000000000367.
BACKGROUND
We previously found differences in the minor allele frequency (MAF) of single-nucleotide polymorphisms (SNPs) in transmembrane protein 196 (TMEM196) between 995 patients with aspirin-tolerant asthma (ATA) and 141 asthmatic patients with NSAID-exacerbated respiratory disease (NERD). In this study, we statistically analyzed the distributions of the genotypes and haplotypes of these SNPs to determine the exact association between TMEM196 genetic variants and the risk for NERD.
MATERIALS AND METHODS
Lewontin's D' and r values were used to measure linkage disequilibrium between the biallelic loci having MAFs more than 0.05, and haplotypes were inferred using the PHASE algorithm (version 2.0). The genotype distribution was analyzed by logistic regression models using age of onset, smoking status (nonsmoker=0, ex-smoker=1, smoker=2), and BMI as covariates. Regression analysis of the association between SNPs and the risk of NERD was analyzed using SPSS version 12.0 and PLINK version 1.9.
RESULTS
The MAF of rs9886152 C>T was significantly lower in NERD than in ATA [24.8 vs. 34.0%, odds ratio=0.64 (0.48-0.85), P=2.07×10, Pcorr=0.048]. The rate of the rs9886152 C>T minor allele was significantly lower in NERD than in ATA [44.0 vs. 56.4% in the codominant model, P=0.002, Pcorr=0.049, odds ratio=0.64 (0.48-0.85)]. An additional three SNPs (rs9639334 A>G, rs9638765 A>G, and rs2097811 G>A) showed similar associations with the risk of NERD. NERD patients had lower frequencies of the rs9639334 A>G minor allele (51.1 vs. 64.4%, P=0.002, Pcorr=0.043), rs9638765 A>G (49.7 vs. 64.2%, P=0.001, Pcorr=0.017), and rs2097811 G>A (51.1 vs. 64.5%, P=0.002, Pcorr=0.04) compared with ATA patients. Patients homozygous for the minor alleles of the four SNPs showed significantly less of an aspirin-induced decrease in forced expiratory volume in one second compared with those homozygous for the common alleles (P=0.003-0.012).
CONCLUSION
The minor alleles of the four SNPs in TMEM196 may exert a protective effect against the development of NERD and may be useful genetic markers to predict the risk of NERD.
背景
我们之前在 995 例阿司匹林耐受型哮喘（ATA）患者和 141 例非甾体抗炎药加重的呼吸道疾病（NERD）哮喘患者中发现跨膜蛋白 196（TMEM196）单核苷酸多态性（SNP）的次要等位基因频率（MAF）存在差异。在这项研究中，我们对这些 SNP 的基因型和单体型分布进行了统计学分析，以确定 TMEM196 遗传变异与 NERD 风险之间的确切关联。
材料和方法
Lewontin 的 D'和 r 值用于测量 MAF 大于 0.05 的双等位基因座之间的连锁不平衡，使用 PHASE 算法（版本 2.0）推断单体型。使用 logistic 回归模型分析基因型分布，使用发病年龄、吸烟状况（非吸烟者=0，前吸烟者=1，吸烟者=2）和 BMI 作为协变量。使用 SPSS 版本 12.0 和 PLINK 版本 1.9 分析 SNP 与 NERD 风险之间的关联的回归分析。
结果
NERD 中 rs9886152 C>T 的 MAF 明显低于 ATA [24.8% vs. 34.0%，优势比=0.64（0.48-0.85），P=2.07×10，Pcorr=0.048]。NERD 中 rs9886152 C>T 次要等位基因的频率明显低于 ATA [在共显性模型中，44.0% vs. 56.4%，P=0.002，Pcorr=0.049，优势比=0.64（0.48-0.85）]。另外三个 SNP（rs9639334 A>G、rs9638765 A>G 和 rs2097811 G>A）与 NERD 风险也有类似的关联。NERD 患者 rs9639334 A>G 次要等位基因（51.1% vs. 64.4%，P=0.002，Pcorr=0.043）、rs9638765 A>G（49.7% vs. 64.2%，P=0.001，Pcorr=0.017）和 rs2097811 G>A（51.1% vs. 64.5%，P=0.002，Pcorr=0.04）的频率均低于 ATA 患者。与常见等位基因相比，四个 SNP 纯合子的次要等位基因的阿司匹林诱导的一秒用力呼气量下降明显较少（P=0.003-0.012）。
结论
TMEM196 中的四个 SNP 的次要等位基因可能对 NERD 的发展具有保护作用，可能是预测 NERD 风险的有用遗传标志物。
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