Table_1_Single-Nucleotide Polymorphisms in LEP and LEPR Associated With Breast Cancer Risk: Results From a Multicenter Case–Control Study in Chinese Females.docx

BackgroundLeptin (LEP) plays a physiological role through its specific receptor (LEPR) and is involved in the occurrence and development of breast cancer. Our current study aimed at determining the influence of single-nucleotide polymorphisms (SNPs) in the genes coding for LEP and LEPR on breast cancer risk.
MethodsIn the present study, 963 breast cancer cases and 953 controls were enrolled. Five SNPs of LEP and two of LEPR were chosen to evaluate the correlation of selected SNPs with breast cancer susceptibility among women in northern and eastern China. Analyses were further stratified by body mass index (BMI), waist–hip rate (WHR), estrogen receptor, and progesterone receptor status. The expression patterns of risk variant-associated genes were detected by expression quantitative trait locus (eQTL) analysis with eQTLGen and The Cancer Genome Atlas database.
ResultsThere were significant differences between breast cancer cases and control groups in the menopausal status and family history of breast cancer. Two SNPs (rs1137101 and rs4655555) of the LEPR gene decreased overall breast cancer risk, and other five SNPs showed no significant association with breast cancer risk. rs1137101 (GA vs. GG; adjusted OR = 0.719, 95% CI = 0.578–0.894, p = 0.003) and rs4655555 (TT vs. AA; adjusted OR = 0.574, 95% CI = 0.377–0.873, p = 0.009) significantly decreased breast cancer risk after Bonferroni correction for multiple testing. In subgroup analyses, the GA and GA + AA genotypes of LEPR rs1137101 associated with decreased breast cancer risk in the subgroup of BMI ≤ 24 kg/m2 or WHR ≥ 0.85 after Bonferroni correction. Furthermore, we found that the expressions of rs4655555-associated gene LEPR and leptin receptor overlapping transcript (LEPROT) were upregulated in breast cancer tumor tissues compared with adjacent normal tissues, and a higher expression of LEPR in tumor tissues was correlated with poor prognosis of breast cancer patients using The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) data.
ConclusionOur study demonstrated that the polymorphisms rs1137101 and rs4655555 located in the LEPR gene decreased breast cancer risk in Chinese females, which might be a research-worthy bio-diagnostic marker and applied for early prediction and risk assessment of breast cancer.

背景 瘦素（Leptin, LEP）通过其特异性受体（瘦素受体, LEPR）发挥生理功能，并参与乳腺癌的发生与发展。本研究旨在探讨编码LEP与LEPR的基因中的单核苷酸多态性（Single-Nucleotide Polymorphisms, SNPs）对乳腺癌发病风险的影响。
方法 本研究共纳入963例乳腺癌患者与953例对照个体。选取LEP基因的5个SNPs及LEPR基因的2个SNPs，评估中国北方与东部地区女性中所选SNPs与乳腺癌易感性的关联。后续分析按体质量指数（Body Mass Index, BMI）、腰臀比（Waist-Hip Ratio, WHR）、雌激素受体及孕激素受体状态进行分层。借助eQTLGen数据库与癌症基因组图谱（The Cancer Genome Atlas, TCGA）数据库，通过表达数量性状基因座（Expression Quantitative Trait Locus, eQTL）分析，检测风险变异相关基因的表达模式。
结果 乳腺癌患者组与对照组在绝经状态及乳腺癌家族史方面存在显著差异。LEPR基因的2个SNPs（rs1137101与rs4655555）可降低总体乳腺癌发病风险，其余5个SNPs与乳腺癌发病风险无显著关联。经多重检验的Bonferroni校正后，rs1137101（GA vs. GG；校正优势比（adjusted OR）=0.719，95%置信区间（95% CI）=0.578~0.894，p=0.003）与rs4655555（TT vs. AA；校正优势比（adjusted OR）=0.574，95%置信区间（95% CI）=0.377~0.873，p=0.009）均可显著降低乳腺癌发病风险。分层分析显示，经Bonferroni校正后，在体质量指数≤24kg/m²或腰臀比≥0.85的亚组中，LEPR rs1137101的GA基因型及GA+AA基因型与乳腺癌发病风险降低相关。此外，借助癌症基因组图谱乳腺浸润性癌（The Cancer Genome Atlas Breast Invasive Carcinoma, TCGA-BRCA）数据集分析发现，与癌旁正常组织相比，rs4655555相关基因LEPR及瘦素受体重叠转录本（Leptin Receptor Overlapping Transcript, LEPROT）在乳腺癌肿瘤组织中的表达显著上调，且肿瘤组织中LEPR高表达与乳腺癌患者不良预后显著相关。
结论 本研究证实，位于LEPR基因上的rs1137101与rs4655555多态性可降低中国女性的乳腺癌发病风险，有望成为具备研究价值的生物诊断标志物，用于乳腺癌的早期预测与风险评估。