| Breast cancer(BC)is the most common malignant tumor in women and is a serious threat to the physical and mental health of women worldwide and in China.According to Global Cancer Statistics 2021,BC has become the most common malignant tumor in women,which accounts for 31%of all new cancers in women.Furthermore,China is undergoing cancer transition with an increasing burden of BC.According to national cancer statistics released by the National Cancer Centre in February 2022,there were approximately 306,000 new cases of BC and up to 72,000 deaths from BC among women nationwide in 2016.There are varieties of factors that can increase the risk of BC,including family history of BC,breastfeeding,secondhand smoke,eating habits,obesity and diabetes mellitus.Based on larger observational studies,obesity increases the risk of breast cancer,particularly in postmenopausal women.Obesity induces the dysfunction of adipocyte,changes the expression levels of adipokines and hormones,which will promote the progress of obesity related-tumors.High expression of leptin(LEP)in obese patients was identified associated with the occurrence of breast cancer.LEP,the circulating product of the obesity gene,is a 16 kDa glycoprotein expressed and secreted primarily by the adipocyte,which exerts its physiological action through leptin receptor(LEPR)and leptin receptor overlapping transcript(LEPROT).LEP plays an important role in body weight homeostasis by influencing food intake,energy expenditure and maintaining constant energy stores.In addition to the regulation of body weight,LEP was also identified to involve in insulin resistance,cancer cells inflammation,oxidative stress,cell proliferation,apoptosis,angiogenesis,and anti-tumor immune regulation.The expression of LEP and LEPR was associated with enhanced cell proliferation,and angiogenesis both in benign and malignant breast epithelial cells.Moreover,high circulating LEP concentration is significantly associated with an increased risk of BC and considered as a potential risk factor associated with obesity and breast cancer.However,in previous studies,the association between single nucleotide polymorphisms(SNPs)in the LEP and LEPR genes and the risk of BC is not consistent.ObjectiveTo investigate the association of SNPs of LEP and LEPR gene with the risk of BC in Chinese Han females.MethodsIn the present study,963 BC cases and 953 controls were enrolled.rs 10244329,rs10954173,rs2167270,rs3828942 and rs4731426 of LEP,and rs1137101 and rs4655555 of LEPR were chosen to evaluate the correlation of selected SNPs with breast cancer susceptibility among women in northern and eastern China by unconditional using logistic regression analysis.Genotyping was performed using the Sequenom Mass ARRAY? SNP system(CapitalBio Technology,China).Stratified analysis was performed according to estrogen receptor(ER)and progesterone receptor(PR)expression status,body mass index(BMI)and waist-hip ratio(WHR).The degree of linkage disequilibrium between SNPs loci of each gene was calculated by using SHEsisPlus software,and the haplotype of SNPs loci of each gene was obtained,and the relationship between haplotype and BC breast cancer susceptibility was analyzed.The expression pattern of risk variants associated gene were detected by expression Quantitative Trait Loci(eQTL)analysis with eQTLGen and the Cancer Genome Atlas(TCGA)database.Results1.There were significant differences in menstrual status and family history of BC between the case and control groups(P<0.05).While other factors were not significantly different between the two groups.It is suggested that multivariate regression model should be used to adjust the above two potential confounders in the subsequent susceptibility analysis of breast cancer and its subtypes.2.All SNPs were consistent with Hardy-Weinberg equilibrium in control group(P>0.05),so all SNPs locus genotypes could be included in the subsequent study.The distribution of LEPR rs1137101 and rs4655555 genotypes in the case group and the control group was statistically significant(P<0.05),while there was no statistical difference in the distribution of other SNPs genotypes.3.LEPR rs1137101 showed a significantly decreased breast cancer risk under dominant genetic model(GA+AA vs GG,adjusted OR=0.722,95%CI=0.5840.893,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 also identified in 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)after Bonferroni correction for multiple testing.Meanwhile,LEPR rs 1137101 and rs4655555 polymorphisms are also associated with the risk of ER+/PR+breast cancer.4.In subgroup analyses,the GA and GA+AA genotype of LEPR rs1137101 associated with decreased breast cancer risk in subgroup of BMI≤24 kg/m2 or WHR>0.85 after Bonferroni correction.The results indicated similar association between rs1137101 genotype and decreased breast cancer risk in both BMI≤24.0 kg/m2&WHR≥0.85(GA+AA vs GG,adjusted OR=0.482,95%CI=0.288-0.807,P=0.006)and BMI>24.0 kg/m2&WHR≥0.85(GA+AA vs GG,adjusted OR=0.563,95%Cl=0.344-0.921,P=0.022)subgroup.5.Haplotype analysis showed that LEPR "GA"(sequence rs1137101-rs4655555)haplotype increased the risk of breast cancer by 19.6%(OR=1.196,95%Cl=1.0301.388)."AT" haplotype can reduce the risk of breast cancer by 24.4%(OR=0.756,95%CI=0.626-0.914).6.Two cis-eQTL genes associated with rs4655555,LEPR and LEPROT,were identified based on the eQTLGen database.Analysis using TCGA data showed that both LEPR and LEPROT were highly expressed in breast cancer tumor tissue compared to matched adjacent normal tissue(P<0.001),Based on TCGA-BRCA data,high expression of LEPR was significantly associated with poor OS in breast cancer patients by Kaplan-Meier survival analysis(HR=1.68,95%Cl:1.01-2.80).ConclusionOur study demonstrated that the polymorphism rs1137101 and rs4655555 located in LEPR gene decreased breast cancer risk in Chinese females,which might be a research-worthy bio-diagnostic marker for Chinese breast cancer patients and applied for early prediction and risk assessment of breast cancer.LEPR rs1137101 may have the potential to reduce the risk of breast cancer in centrally obese women,providing a new idea for the prevention of obesity-associated breast cancer. |
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