| Purpose:To investigate the associations of lung cancer risk-related single nucleotide polymorphisms (SNPs) and their interactions with polycyclic aromatic hydrocarbons (PAHs) and microRNAs (miRNA) expression levels with the levels of oxidative stress and genetic damage.Methods:We cross-sectionally investigated the associations between28SNPs from published genome-wide association studies for lung cancer in Asians and the levels of oxidative stress and genetic damage in1,557coke oven workers in China. The interactions of those SNPs with PAHs and miRNAs expression levels to oxidative stress and genetic damage levels were further analyzed. Urinary PAH metabolites and plasma benzo[a]pyrene-r-7,t-8,c-10-tetrahydrotetrol-albumin (BPDE-Alb) adducts, which were measured by gas chromatography-mass spectrometry and sandwich enzyme-linked immunosorbent assay, respectively, were used to assess the exposure levels of PAHs. The expression levels of miRNAs were measured by qRT-PCR. Urinary8-isoprostane (8-iso-PG) and8-hydroxydeoxyguanosine (8-OHdG) were biomarkers of oxidative stress, which were measured by enzyme-linked immunosorbent assay and high performance liquid chromatography, respectively. Olive Tail Movement (OTM) and micronuclei frequency, determined by alkaline comet assay and cytokinesis-block micronucleus assay, respectively, were used to assess the levels of genetic damage. Association analysis was performed by general linear models. False discovery rate (FDR) adjustment was used for multiple comparisons. Results:13q12.12-rs753955C was suggestively associated with elevated8-OHdG levels after FDR adjustment (P=0.003for the genotype term in the adjusted model; β=0.297,95%confidence interval (CI,0.124-0.471), P=0.001for the comparison of CC vs. TT).9p21-rs1333040C,10p14-rs1663689G, and15q25.1-rs3813572G were significantly associated with lower micronuclei frequency after FDR adjustment (P values were0.002,0.001, and0.005, respectively). Subjects carrying rs1333040TC and TC+CC genotype had lower micronuclei frequency than those with TT genotype (β=-0.09,95%CI-0.146to-0.035, P=0.001for the comparison of TC vs. CC; β=-0.066,95%CI-0.118to-0.014, P=0.013for the comparison of TC vs. TC+CC). Compared with10p14-rs1663689AA genotype, GG genotype decreased micronuclei frequency (β=-0.09,95%CI-0.224to-0.065, P<0.001). Lower micronuclei frequency was observed in individuals carrying at least one15q25.1-rs3813572-G allele than those with AA genotype (β=-0.094,95%CI-0.151to-0.038, P=0.001).The interactions of rs36600and rs4809957with the sum of monohydroxy polycyclic aromatic hydrocarbons (∑OH-PAHs) were associated with the level of8-iso-PG (both interaction<0.001). Stronger effect of∑OH-PAHs on urinary8-iso-PG levels was observed in subjects with genotype of rs36600CT+TT and rs4809957GA/AA (rs36600CT+TT:β=-0.04,95%CI0.031-0.048, P<0.001; rs4809957:GA, β=-0.031,95%CI0.027-0.036, P<0.001, AA, β=-0.039,95%CI0.032-0.046, P<0.001) than those with rs36600CC and rs4809957GG genotypes (rs36600CC:β=-0.025,95%CI0.022-0.028, P<0.001; rs4809957GG:β=0.019,95%CI0.015-0.023, P<0.001). A significant interaction was observed between10p14-rs1663689and∑OH-PAHs to8-OHdG levels (Pinteraction=0.002). The∑OH-PAHs had much less effect on the level of urinary8-OHdG in individuals carrying at least one mutant allele G of rs1663689than those with wild homozygous genotype AA (AA:β=0.037,95%CI,0.031-0.044; AG:β=0.024,95%CI,0.020-0.029;GG:β=0.023,95%CI,0.015-0.030).3q29-rs2131877,5q31-rs247008,3q28-rs4488809,20q13-rs4809957,10q25.2-rs7086803, and17q24.3-rs7216064can modify the associations between plasma BPDE-Alb adducts and OTM levels (Pinteraction values were<0.001,0.001,0.007,0.002,0.008, and<0.001, respectively). BPDE-Alb adducts can increase OTM levels only in individuals with genotypes of rs2131877TT/TC, rs247008TT, rs4488809TC, rs4809957GA, rs7086803GA+AA, and rs7216064AA (P values were0.002,0.002,<0.001,0.001,0.001,0.001, and <0.001, respectively). Interactions of TERT-rs2736100, VTI1A-rs7086803, and BPTF-rs7216064with BPDE-Alb adducts were associated with micronuclei frequency (all pinteraction<0.001). Stronger effect of BPDE-Alb adducts on micronuclei frequency was observed in individuals with genotype of rs2736100GG, rs7086803GA+AA, and rs7216064AA than those with rs2736100TT/Tg, rs7086803GG, and rs7216064AG+GG genotypes.SNP rs4809957interacted with miR-28-5p, jointly regulating OTM levels. SNP rs4809957increased OTM levels only in high expression group of miR-28-5p. Rs667282-miR-27a-3p, rs11080466-, rs6495309-, and rs667282-miR-28-5p interactions were significantly associated with micronuclei frequency. SNP rs11080466, rs6495309, and rs667282were associated with micronuclei frequency only in high expression groups of miRNAs. No significant interactions were observed between these genetic variants and miRNAs to the levels of oxidative stress.Conclusions:lung cancer risk-related SNPs were associated with the levels of oxidative stress and genetic damage. These SNPs could regulate the effects of PAHs and miRNAs on oxidative stress and genetic damage levels. |
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