酚类暴露与基因多态性交互作用对肾功能的影响  

Effect of phenol exposure and single nucleotide polymorphisms interaction on renal function

作　　者：张芾炜 王文卓 蔡晓敏 王璐 何恒 钟荣[1] 田剑波 朱颖 缪小平[1] ZHANG Fuwei;WANG Wenzhuo;CAI Xiaomin;WANG Lu;HE Heng;ZHONG Rong;TIAN Jianbo;ZHU Ying;MIAO Xiaoping(Department of Epidemiology and Biostatistics,School of Public Health,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,China;Department of Epidemiology and Health Statistics,School of Public Health,Fujian Medical University,Fuzhou 350108,China;Department of Epidemiology and Health Statistics,School of Public Health,Wuhan University,Wuhan 430071,China)

机构地区：[1]华中科技大学同济医学院公共卫生学院流行病与卫生统计学系,武汉430030 [2]福建医科大学公共卫生学院流行病与卫生统计学系,福州350108 [3]武汉大学公共卫生学院流行病与卫生统计学系,武汉430071

出　　处：《中华疾病控制杂志》2024年第11期1241-1249,共9页Chinese Journal of Disease Control & Prevention

基　　金：国家重点研发计划(2022YFA0806601)。

摘　　要：目的探究双酚A(bisphenol A,BPA)、双酚F(bisphenol F,BPF)、三氯生(triclosan,TCS)暴露与基因位点多态性的交互作用对肾功能的影响。方法2016—2021年在华中科技大学同济医学院附属同济医院的体检人群中,招募了414名成年人作为研究对象,通过问卷形式收集人群信息,采集其尿液样本。检测研究对象尿液样本中3种酚类暴露物(BPA、BPF和TCS)的内暴露水平。测定血清肌酐水平,计算估算的肾小球滤过率(estimated glomerular filtration rate,eGFR)作为肾功能的指标。提取研究对象血液样本中的DNA进行高通量基因分型,并进行基因组填补和质量控制,通过全基因组关联研究分析影响eGFR水平的基因-环境交互作用,最后对显著性和提示性遗传位点进行位置和功能注释,进而探究其相关生物学功能。结果通过高通量基因分型和基因型填补后,共得到414例样本的4135024个单核苷酸多态性(single nucleotide polymorphisms,SNPs)位点的基因型数据。在进一步鉴定中发现3个与BPA在影响肾功能水平上存在交互作用的SNPs位点(rs60391380、rs56108314和rs73082740),其位于4p16.3染色体区段并靠近ADRA2C基因,其中最显著的是rs60391380(β交互作用=-0.042,95%CI:-0.057~-0.028,P=1.565×10^(-8)),结合表观修饰推测该遗传位点可能与BPA发生交互作用,激活其调控元件的功能,上调ADRA2C基因的表达,进而影响肾功能。本研究还探寻到844个提示性BPA交互作用位点(P<5×10^(-6))。在eGFR全基因组关联分析中发现与BPF存在交互作用的提示性位点52个,未发现显著性位点;对于TCS未发现存在交互作用的显著性和提示性位点。结论在人群中,BPA暴露与遗传变异存在基因-环境交互作用,共同影响肾功能。未发现BPF和TCS暴露存在影响肾功能水平的基因-环境交互作用。Objective To investigate of the interaction between exposure to bisphenol A(BPA),bisphenol F(BPF),triclosan(TCS)and gene locus polymorphism on renal function.Methods A total of 414 adults were recruited as research subjects from the physical examination population of Tongji Hospital affiliated with Tongji Medical College of Huazhong University of Science and Technology between 2016 and 2021.Population information was collected through questionnaires,and urine samples were obtained for analysis.The internal exposure levels of three phenolic compounds,namely BPA,BPF,and TCS,were subsequently measured in the urine samples of the study subjects.Serum creatinine levels were measured to determine renal function,and eGFR was calculated as an indicator.Blood samples were taken from research subjects to extract DNA for high-throughput genotyping,genome filling,and quality control.Genome-wide association studies(GWAS)were then conducted to analyze gene-environment interactions affecting eGFR levels.Finally,the obtained significant and suggestive genetic loci were annotated by location and function to explore their related biological functions.Results Following highthroughput genotyping and genotype filling,414 samples were obtained with genotype data for 4135024 single nucleotide polymorphisms(SNPs)loci.During further identification,three SNPs loci(rs60391380,rs56108314,and rs73082740)were found to have a significant interaction with BPA in relation to renal function.These loci were located in the 4p16.3 chromosome segment,close to the ADRA2C gene.The most significant interaction effect was found for rs60391380,with a beta value of-0.042(-0.057--0.028)and a P-value of 1.565×10^(-8).Based on epigenetic modifications,it was speculated that this genetic locus might interact with BPA,activate its regulatory elements,and upregulate the expression of ADRA2C,thereby affecting renal function.Additionally,844 BPA interaction sites were explored,with suggestive results(P<5×10^(-6)).In the eGFR genome-wide association analysis,52 l

关 键 词：酚类暴露 基因-环境交互作用 单核苷酸多态性 慢性肾脏病 估算的肾小球滤过率 

分 类 号：R181[医药卫生—流行病学]