The ketone metabolism pathway is a principle procedure in physiological homeostasis and induces cancer cells to switch between glycolysis and oxidative phosphorylation for energy production. We conducted a two‐phase analysis for associations between genetic variants in the ketone metabolism pathway genes and survival of nonsmall cell lung cancer (NSCLC) by analyzing genotyping data from two published genome‐wide association studies (GWASs). In the discovery, we used a genotyping dataset from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial in the multivariable Cox proportional hazards regression analysis. We used Bayesian false discovery probability (≤0.80) for multiple testing correction to evaluate associations between 25,819 (2,176 genotyped and 23,643 imputed) single‐nucleotide polymorphisms (SNPs) in 162 genes and survival of 1,185 NSCLC patients. Subsequently, we validated the identified significant SNPs with an additional 984 NSCLC patients from the Harvard Lung Cancer Susceptibility GWAS study. Finally, we found that three independent and potentially functional SNPs in three different genes (i.e., PLIN2 rs7867814 G>A, SULT2A1 rs2547235 C>T and UGT1A9 rs2011404 C>T) were independently associated with risk of death from NSCLC, with a combined hazards ratio of 1.22 [95% confidence interval = 1.09–1.36 and p = 0.0003], 0.82 (0.74–0.91 and p = 0.0002) and 1.21 (1.10–1.33 and p = 0.0001), respectively. Additional expression quantitative trait loci analysis found that the survival‐associated PLIN2 rs7867814 GA + AA genotypes, but not the genotypes of other two SNPs, were significantly associated with increased mRNA expression levels (p = 0.005). These results indicated that PLIN2 variants may be potential predictors of NSCLC survival through regulating the PLIN2 expression.

中文翻译：

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酮途径的PLIN2，SULT2A1和UGT1A9基因中的潜在功能遗传变异和非小细胞肺癌的生存。

酮代谢途径是生理稳态中的一个基本程序，可诱导癌细胞在糖酵解和氧化磷酸化之间切换以产生能量。我们通过分析来自两个已发表的全基因组关联研究（GWAS）的基因分型数据，对酮代谢途径基因的遗传变异与非小细胞肺癌（NSCLC）的生存之间的关联进行了两阶段分析。在这项发现中，我们在多变量Cox比例风险回归分析中使用了来自前列腺，肺，结肠直肠和卵巢癌筛查试验的基因分型数据集。我们使用贝叶斯错误发现概率（≤0.80）进行了多次测试校正，以评估25,819（2,176个基因分型与23个基因分型，162个基因中的643个估算的单核苷酸多态性（SNP）和1,185名NSCLC患者的存活率。随后，我们与来自哈佛大学肺癌易感性GWAS研究的984名NSCLC患者一起验证了已鉴定出的重要SNP。最后，我们发现了三个不同基因中的三个独立且具有潜在功能的SNP（即PLIN2 rs7867814 G> A，SULT2A1 rs2547235 C> T和UGT1A9 rs2011404 C> T）与NSCLC死亡风险独立相关，综合危险比为1.22 [95％置信区间= 1.09–1.36和p = 0.0003]，分别为0.82（0.74-0.91和p = 0.0002）和1.21（1.10-1.33和p = 0.0001）。进一步的表达定量性状基因座分析发现，与生存相关的PLIN2 rs7867814 GA + AA基因型与其他两个SNP的基因型无关，而与mRNA表达水平升高显着相关（p = 0.005）。这些结果表明PLIN2这些变体可能是通过调节PLIN2表达来预测NSCLC存活的潜在指标。