Refining susceptibility loci of chronic obstructive pulmonary disease with lung eqtls.
Refining susceptibility loci of chronic obstructive pulmonary disease with lung eqtls.
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DOI：
10.1371/journal.pone.0070220
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Bossé Y
中科院分区：
文献类型：
--
作者：
Lamontagne M;Couture C;Postma DS;Timens W;Sin DD;Paré PD;Hogg JC;Nickle D;Laviolette M;Bossé Y
慢性阻塞性肺疾病（COPD）是全球第四大死亡原因。最近的全基因组关联研究（GWAS）已经确定了与COPD相关的强大易感基因座。然而，介导这些基因座所赋予的风险的机制仍有待发现。本研究的目的是确定与COPD相关的易感基因座内的致病基因/变异。在发现队列中，从接受肺手术的患者中获得了500个非肿瘤肺标本的全基因组基因表达谱。来自相同患者的血液DNA被基因分型为120万个SNP。在基因分型和基因表达质量控制过滤器之后，分析了409个样品。肺表达数量性状基因座（eQTL）被鉴定并覆盖到来自GWAS的三个COPD易感基因座上; 4 q31（HHIP）、4 q22（FAM 13 A）和19 q13（RAB 4 B、EGLN 2、MIA、CYP 2A 6）。在两个独立的数据集（n = 363和339）中复制了显著的eQTL。 4 q31上与COPD和肺功能相关的SNPs（rs 1828591，rs 13118928）与HHIP的mRNA表达相关。FAM 13 A基因mRNA表达水平与4 q22的rs 2045517单核苷酸多态性相关，但未达到统计学意义。在19 q13处，利用EGLN 2检测到显著的eQTL。总之，这项研究支持HHIP，FAM 13 A和EGLN 2分别是4 q31，4 q22和19 q13上最可能的COPD致病基因。在本研究中鉴定的强肺eQTL SNP将需要在病例对照研究中测试与COPD的关联。还需要进一步的功能研究来了解疾病相关变异体调控的基因在COPD中的作用。
Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of mortality worldwide. Recent genome-wide association studies (GWAS) have identified robust susceptibility loci associated with COPD. However, the mechanisms mediating the risk conferred by these loci remain to be found. The goal of this study was to identify causal genes/variants within susceptibility loci associated with COPD. In the discovery cohort, genome-wide gene expression profiles of 500 non-tumor lung specimens were obtained from patients undergoing lung surgery. Blood-DNA from the same patients were genotyped for 1,2 million SNPs. Following genotyping and gene expression quality control filters, 409 samples were analyzed. Lung expression quantitative trait loci (eQTLs) were identified and overlaid onto three COPD susceptibility loci derived from GWAS; 4q31 (HHIP), 4q22 (FAM13A), and 19q13 (RAB4B, EGLN2, MIA, CYP2A6). Significant eQTLs were replicated in two independent datasets (n = 363 and 339). SNPs previously associated with COPD and lung function on 4q31 (rs1828591, rs13118928) were associated with the mRNA expression of HHIP. An association between mRNA expression level of FAM13A and SNP rs2045517 was detected at 4q22, but did not reach statistical significance. At 19q13, significant eQTLs were detected with EGLN2. In summary, this study supports HHIP, FAM13A, and EGLN2 as the most likely causal COPD genes on 4q31, 4q22, and 19q13, respectively. Strong lung eQTL SNPs identified in this study will need to be tested for association with COPD in case-control studies. Further functional studies will also be needed to understand the role of genes regulated by disease-related variants in COPD.
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影响因子：
30.8
作者：
Fairfax, Benjamin P.;Makino, Seiko;Radhakrishnan, Jayachandran;Plant, Katharine;Leslie, Stephen;Dilthey, Alexander;Ellis, Peter;Langford, Cordelia;Vannberg, Fredrik O.;Knight, Julian C.
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1.2
作者：
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通讯作者：
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2.2
作者：
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