The role of abnormal methylation of FGFR2 in the association between nickel exposure and non-syndromic cleft lip and/or palate
PAN Yaquan, NI Wenli, YANG Wenlei, JIN Lei, LI Zhiwen, REN Aiguo, WANG Linlin
Institute of Reproductive & Child Health; National Health Commission Key Laboratory of Reproductive Health; Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, China
Abstract：Objective To explore the role of abnormal methylation of FGFR2 in the association between nickel exposure and non-syndromic cleft lip and/or palate.Methods A two-stage case-control study was conducted, which was based on a birth defect surveillance program in Shanxi Province, China. The subjects were cases of non-syndromic cleft lip and/or palate (NSCL/P) and controls without congenital malformations. In the first stage, 10 cases and 10 controls were included, and 850k MethylationEPIC BeadChip was used for the quantification of DNA methylation levels of umbilical cord blood. In the second stage, methylated levels in target gene was detected with a larger number of samples (24 cases and 57 controls), and Sequenom MassARRAY time-flight mass spectrometry array gene analysis platform was employed to verify the differential methylation gene screened in the first stage.Results In the first stage, significant difference of the methylation level in 2 CpG sites of FGFR2 was detected. In the second stage, we testified that the average methylation level of FGFR2 in the case group (3.80%) was higher than that in the control group (3.36%), P＜0.05. Logistic regression model adjusting for folic acid supplementation, smoking and drinking showed that FGFR2 hypermethylation was associated with increased risk of NSCL/P. Nickel concentration was positively correlated with the methylation level of FGFR2, (rs=0.229, P＜0.05), but the Linear regression model did not support it.Conclusion Increased methylation level in FGFR2 may elevate the risk of NSCL/P; no significant effect of nickel exposure on the methylation level of FGFR2 was found.
潘亚权, 倪文丽, 杨文蕾, 靳蕾, 李智文, 任爱国, 王琳琳. FGFR2基因异常甲基化在镍暴露与非综合征唇腭裂关联中的作用[J]. 中国生育健康杂志, 2021, 32(5): 442-446.
PAN Yaquan, NI Wenli, YANG Wenlei, JIN Lei, LI Zhiwen, REN Aiguo, WANG Linlin. The role of abnormal methylation of FGFR2 in the association between nickel exposure and non-syndromic cleft lip and/or palate. Chinese Journal of Reproductive Health, 2021, 32(5): 442-446.
1 Wang M,Yuan Y,Wang Z,et al.Prevalence of orofacial clefts among live births in china:a systematic review and meta-analysis.Birth Defects Res,2017,109:1011-1019. 2 Dixon M,Marazita M,Beaty T,et al.Cleft lip and palate:understanding genetic and environmental influences.Nat Rev Genet,2011,12:167-178. 3 Candotto V,Oberti L,Gabrione F,et al.Current concepts on cleft lip and palate etiology.J Biol Regul Homeost Agents,2019,33:145-151. 4 Ni W,Yang W,Yu J,et al.Umbilical cord concentrations of selected heavy metals and risk for orofacial clefts.Environ Sci Technol.2018,52:10787-10795. 5 Cao Z,Fang Y,Lu Y,et al.Exposure to nickel oxide nanoparticles induces pulmonary inflammation through NLRP3 inflammasome activation in rats.Int J Nanomedicine,2016,11:3331-3346. 6 Beshir S,Ibrahim K,Shaheen W,et al.Hormonal perturbations in occupationally exposed nickel workers.Open Access Maced J Med Sci,2016,4:307-311. 7 Dai L,Mehta A,Mordukhovich I,et al.Differential DNA methylation and PM2.5 species in a 450K epigenome-wide association study.Epigenetics,2017,12:139-148. 8 Xu Z,Lie R,Wilcox A,et al.A comparison of DNA methylation in newborn blood samples from infants with and without orofacial clefts.Clin Epigenetics,2019,11:40. 9 Wang L,Lin S,Zhang J,et al.Fetal DNA hypermethylation in tight junction pathway is associated with neural tube defects:A genome-wide DNA methylation analysis.Epigenetics,2017,12:157-165. 10 Serra-Juhé C,Cuscó I,Homs A,et al.DNA methylation abnormalities in congenital heart disease.Epigenetics,2015,10:167-177. 11 Mazzio EA,Soliman KF.Basic concepts of epigenetics:impact of environmental signals on gene expression.Epigenetics,2012,7:119-130. 12 Riley BM,Mansilla MA,Ma J,et al.Impaired FGF signaling contributes to cleft lip and palate.Proc Natl Acad Sci U S A,2007,104:4512-4517. 13 Yin R,Mo J,Dai J,et al.Nickel(ii) inhibits the oxidation of DNA 5-methylcytosine in mammalian somatic cells and embryonic stem cells.Metallomics,2018,10:504-512. 14 Alvizi L,Ke X,Brito LA,et al.Differential methylation is associated with non-syndromic cleft lip and palate and contributes to penetrance effects.Sci Rep,2017,7:2441. 15 Li Y,Deng Y,Deng C,et al.Association of long interspersed nucleotide element-1 and interferon regulatory factor 6 methylation changes with nonsyndromic cleft lip with or without cleft palate.Oral Dis,2018,25:215-222. 16 Stanier P,Pauws E.Development of the lip and palate:FGF signalling.Front Oral Biol,2012,16:71-80. 17 Weng M,Chen Z,Xiao Q,et al.A review of FGF signaling in palate development.Biomed Pharmacother,2018,103:240-247. 18 Jin JZ,Lei Z,Lan ZJ,et al.Inactivation of Fgfr2 gene in mouse secondary palate mesenchymal cells leads to cleft palate.Reprod Toxicol,2018,77:137-142. 19 Rice R,Spencer-Dene B,Connor EC,et al.Disruption of Fgf10/Fgfr2b-coordinated epithelial-mesenchymal interactions causes cleft palate.J Clin Invest,2004,113:1692-1700. 20 Sharp G C,Ho K,Davies A,et al.Distinct DNA methylation profiles in subtypes of orofacial cleft.Clin Epigenetics,2017,9:63.
