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<p>This study aimed to investigate the relationship between methylation quantitative trait loci (meQTL) and lung adenocarcinoma (LUAD) susceptibility. Candidate SNPs linked to differentially methylated CpG sites in LUAD were identified through meQTL datasets. Genome-wide association study (GWAS) data were analyzed to assess the correlation between selected meQTLs and LUAD risk. The effects of target genes on malignant LUAD phenotypes were examined through both in vitro and in vivo experiments. Additionally, machine learning and radiomics models were employed to evaluate the association of target genes on LUAD progression. The variant A allele of rs939408 was associated with decreased methylation levels of cg09596674 in <i>LRRC2</i> (β &lt; 0, <i>P</i> &lt; 0.001). While cg09596674 was highly methylated, <i>LRRC2</i> showed lower expression in LUAD tumor tissues. Consistently, a negative correlation was observed between methylation of cg09596674 and <i>LRRC2</i> expression (r = −0.32, <i>P</i> &lt; 0.001), indicating that lower methylation of cg09596674 modulated by rs939408 may reduce non-smoking LUAD risk (OR = 0.89, <i>P</i> = 0.019). Increased <i>LRRC2</i> expression inhibited LUAD cell line malignancy and suppressed tumor growth in mice. Furthermore, lower <i>LRRC2</i> expression was linked to metastasis (<i>P</i> = 0.02) and higher levels of two poorer survival-related imaging features (<i>P</i> = 0.03). The meQTL rs939408 may modulate DNA methylation of <i>LRRC2</i>, thereby influencing its expression and potentially affecting non-smoking LUAD risk. These findings offer valuable insights into the role of meQTLs in LUAD carcinogenesis.</p>

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Integrated genetic and epigenetic analysis identifies that rs939408 affects non-smoking lung adenocarcinoma risk by modulating the DNA methylation of LRRC2

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月17日

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  • Lei Zhang,
  • Zhenyu Li,
  • Yanchi Wang,
  • Mingjiong Zhang,
  • Haoyan Chen,
  • Yifan Cheng,
  • Qiong Chen,
  • Baosheng Cui,
  • Jiahao Liu,
  • Haiyan Gong,
  • Rui Zhu,
  • Tian Tian,
  • Yan Zhang,
  • Shengguang Ding,
  • Yu Duan,
  • Shuangshuang Wu,
  • Minjie Chu

摘要

This study aimed to investigate the relationship between methylation quantitative trait loci (meQTL) and lung adenocarcinoma (LUAD) susceptibility. Candidate SNPs linked to differentially methylated CpG sites in LUAD were identified through meQTL datasets. Genome-wide association study (GWAS) data were analyzed to assess the correlation between selected meQTLs and LUAD risk. The effects of target genes on malignant LUAD phenotypes were examined through both in vitro and in vivo experiments. Additionally, machine learning and radiomics models were employed to evaluate the association of target genes on LUAD progression. The variant A allele of rs939408 was associated with decreased methylation levels of cg09596674 in LRRC2 (β < 0, P < 0.001). While cg09596674 was highly methylated, LRRC2 showed lower expression in LUAD tumor tissues. Consistently, a negative correlation was observed between methylation of cg09596674 and LRRC2 expression (r = −0.32, P < 0.001), indicating that lower methylation of cg09596674 modulated by rs939408 may reduce non-smoking LUAD risk (OR = 0.89, P = 0.019). Increased LRRC2 expression inhibited LUAD cell line malignancy and suppressed tumor growth in mice. Furthermore, lower LRRC2 expression was linked to metastasis (P = 0.02) and higher levels of two poorer survival-related imaging features (P = 0.03). The meQTL rs939408 may modulate DNA methylation of LRRC2, thereby influencing its expression and potentially affecting non-smoking LUAD risk. These findings offer valuable insights into the role of meQTLs in LUAD carcinogenesis.