Low-Frequency Coding Variants at 6p21.33 and 20q11.21 Are Associated with Lung Cancer Risk in Chinese Populations
Low-Frequency Coding Variants at 6p21.33 and 20q11.21 Are Associated with Lung Cancer Risk in Chinese Populations
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DOI：
10.1016/j.ajhg.2015.03.009
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发表时间：
2015-05-07
影响因子：
9.8
通讯作者：
Shen, Hongbing
中科院分区：
文献类型：
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作者：
Jin, Guangfu;Zhu, Meng;Shen, Hongbing
全基因组关联研究已成功识别出与肺癌风险相关的常见变异子集。然而，这些变异只能解释肺癌遗传性的一小部分。有人提出，低频率或罕见的变异可能有很强的影响，并有助于缺失的遗传力。为了评估低频或罕见变异在肺癌发展中的作用，我们分析了在发现阶段代表1，348名肺癌受试者和1，998名对照受试者的外显子组芯片，随后在复制阶段评估了另外4，699名受影响受试者和4，915名对照受试者的有希望的关联。对次要等位基因频率小于0.05的编码变体进行单变体和基于基因的分析。我们在BAT 2中发现了三个低频错义变体，（rs 9469031，c.1544C>T [p.Pro515Leu];比值比[OR] = 0.55，p = 1.28 x 10（-10）），FKBPL（rs200847762，c.410C>T [p.Pro137Leu]; OR = 0.25，p = 9.79 x 10（-12）），和BPIFB1（rs6141383，c.850G>A [p.Val284Met]; OR = 1.72，p = 1.79 x 10（-7））;这些变异与肺癌风险相关。BAT 2中的rs 9469031和BPIFB 1中的rs6141383也与肺癌发病年龄相关（分别为p = 0.001和0.006）。BAT 2和FKBPL在6p21.33和BPIFB 1在20q11.21在肺肿瘤和配对正常组织中差异表达。基于基因的分析显示，FKBPL，其中两个独立的变体被确定，可能解释与肺癌风险在6p21.33的关联。我们的研究结果强调了低频变异在肺癌易感性中的重要作用，并表明6p21.33和20q11.21的候选基因与肺癌发生具有潜在的生物学相关性。
Genome-wide association studies have successfully identified a subset of common variants associated with lung cancer risk. However, these variants explain only a fraction of lung cancer heritability. It has been proposed that low-frequency or rare variants might have strong effects and contribute to the missing heritability. To assess the role of low-frequency or rare variants in lung cancer development, we analyzed exome chips representing 1,348 lung cancer subjects and 1,998 control subjects during the discovery stage and subsequently evaluated promising associations in an additional 4,699 affected subjects and 4,915 control subjects during the replication stages. Single-variant and gene-based analyses were carried out for coding variants with a minor allele frequency less than 0.05. We identified three low-frequency missense variants in BAT2 (rs9469031, c.1544C>T [p.Pro515Leu]; odds ratio [OR] = 0.55, p = 1.28 x 10(-10)), FKBPL (rs200847762, c.410C>T [p.Pro137Leu]; OR = 0.25, p = 9.79 x 10(-12)), and BPIFB1 (rs6141383, c.850G>A [p.Val284Met]; OR = 1.72, p = 1.79 x 10(-7)); these variants were associated with lung cancer risk. rs9469031 in BAT2 and rs6141383 in BPIFB1 were also associated with the age of onset of lung cancer (p = 0.001 and 0.006, respectively). BAT2 and FKBPL at 6p21.33 and BPIFB1 at 20q11.21 were differentially expressed in lung tumors and paired normal tissues. Gene-based analysis revealed that FKBPL, in which two independent variants were identified, might account for the association with lung cancer risk at 6p21.33. Our results highlight the important role low-frequency variants play in lung cancer susceptibility and indicate that candidate genes at 6p21.33 and 20q11.21 are potentially biologically relevant to lung carcinogenesis.