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

Liang Li,Fei Zhou,Gengshen Yin,Feng Jin,Hong Liang,Haibo Wang,Jianguo Zhang,Xingchen Meng,Guolou Li,Fei Wang,Xuening Duan,Wenzhong Zhou,Chunmiao Ye,Xiang Wang,Hongchuan Jiang,Xuchen Cao,Jinhai Tang,Liyuan Liu,Chao Zheng,Qitang Wang,Zhimin Fan,Zhongbing Ma,Shuya Huang,Shude Cui,Zhenlin Yang,Geng Chen ,Shuchai Zhu ,Yuzhi Xiang ,Wenqi Zuo ,Fei Tian ,Shu Wang ,Zhengping Yu

doi:10.3389/fonc.2022.809570

Abstract

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.

Highlights

According to Global Cancer Statistics 2021, breast cancer is the most commonly diagnosed cancer worldwide, which accounts for 30% of all new cancers in women
Among the 7 single-nucleotide polymorphisms (SNPs), LEPR rs1137101 showed a significantly decreased breast cancer risk under the dominant genetic model (GA + AA vs. GG, adjusted Odds ratios (OR) = 0.722, 95% confidence interval (95% CI) = 0.584–0.893, p = 0.003) and co-dominant genetic model (GA vs. GG, adjusted OR = 0.719, 95% CI = 0.578–0.894, p = 0.003)
For LEPR rs4655555, a significant association with decreased breast cancer risk was identified in the co-dominant genetic model (TT vs. AA, adjusted OR = 0.574, 95% CI = 0.377–0.873, p = 0.009) and recessive model (TT vs. TA + AA, adjusted OR = 0.595, 95% CI = 0.394–0.899, p = 0.014)

Summary

Introduction

According to Global Cancer Statistics 2021, breast cancer is the most commonly diagnosed cancer worldwide, which accounts for 30% of all new cancers in women. Breast cancer is the second leading cause of cancer death among women [1]. Based on larger observational studies, obesity is associated with a higher risk of developing breast cancer, in postmenopausal women [5, 6]. A high expression of leptin (LEP) and low levels of adiponectin in obese patients were identified associated with the occurrence of breast cancer [8]. Leptin (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

Methods

Results

Conclusion