Association Of IL-12/IFN-γ Axis Gene Polymorphisms With Susceptibility To Hand,Foot And Mouth Disease Infected By EV71

Objective This study investigated the association of genetic polymorphisms of the five genes on IL-12/IFN-y axis, including interleukin 12 B (IL-12B), interleukin 12 receptor beta 1 (IL-12RB1), signal transducer and activator of transcription 4 (STAT4), interferon gamma receptor 2 (IFNGR2), signal transducer and activator of transcription 1 (STAT1), with the susceptibility to EV71 infected HFMD.Methods We enrolled 145 EV71 infected HFMD samples,104 EV71 recessive infections and 89 control samples in Guangxi Zhuang population. Serum EV71 and CoxA16 special antibodies were measured using ELISA. Altogether 27 single nucleotide polymorphisms (SNPs) of IL-12/IFN-y axis were detected by an improved multiplex ligation detection reaction (imLDRTM) technique. The genotypes and alleles frequencies were analyzed by statistic and the association between them and susceptibility to EV71 infected HFMD was evaluated.Results (1) The differences of the genotypes and alleles frequencies of six SNPs (rs12461312, rs17882555, rs1870063, rs2305740, rs2305741, rs3746190) in IL-12RB1 were statistically significant (P<0.05) between EV71 infected HFMD group and control group, and the frequencies of rs12461312 allele C,rs17882555 allele G,rs1870063 allele C,rs2305740 allele A, rs2305741 allele G and rs3746190 allele G in EV71 infected HFMD group were significantly higher than control group; while the differences were no significant (P>0.05) between EV71 recessive infection group and control group and also between EV71 infected HFMD group and EV71 recessive infections. (2) The genotype frequency of rs 11676659 in STAT4 was significantly different (P<0.05) and the allele frequency was not (P>0.05) between EV71 infected HFMD group and control group. The genotype frequency distribution was significantly different (P=0.049), and the allele frequency was not between EV71 infected HFMD group and EV71 recessive group. The frequency of genotype AA in EV71 infected HFMD group was lower than in EV71 recessive group and in control group. The genotype and allele frequencies of rs 11676659 were not different (P>0.05) between EV71 recessive group and control group. (3) EV71 infected HFMD group and EV71 recessive infection group compared with the control group respectively, the distribution of genotypes and allele frequencies of IFNGR2 locus rs9808753 were statistically significant (P<0.05). The genotype AA and allele A frequencies in the two infected groups were higher than control group. The genotype and allele frequencies were not significantly different (P>0.05) among EV71 infected HFMD group and EV71 recessive group. (4) IL-12RB1gene loci rs3746190(A/G), rsl2461312(A/C), rsl7882555(A/G), rs1870063(C/T), rs2305740(A/G), rs2305741(A/G) were tested linkage disequilibrium (LD) analysis:the six SNPs had strong LD (D>0.8 and r2>0.8).The haplotype of GCGCAG is the risk factor of EV71 infected HFMD [P=0.017, OR (95%CI)：2.116 (1.131-3.956)]. (5) Between EV71 infected HFMD group and control group, the allele frequencies of rs375947, rs383483, rs391410 and rs401502 were different (P<0.05).In EV71 infected HFMD group, the frequencies of rs375947 allele A, rs383483 allele A, rs391410 allele G and rs401502 allele C were higher than control group, and the genotype frequencies were not different (P>0.05).The genotype and allele frequencies of the four SNPs were not different (P>0.05) between EV71 recessive group and control group and also between EV71 infected HFMD group and EV71 recessive group.The genotypes and alleles frequencies of other 15 SNPs were not significantly different (P>0.05) between the two infected groups and control group.Conclusions (1) IL-12RB1 gene six polymorphisms (rs12461312, rs17882555, rs1870063, rs2305740, rs2305741, rs3746190) might associate with susceptibility to EV71 infected HFMD. Respectively, genotype CC and allele C, genotype GG and allele G, genotype CC and allele C, genotype AA and allele A, genotype GG and allele G, genotype GG and allele G were risk factors for EV71 infected HFMD. (2) STAT4 gene polymorphism rs 11676659 might associate with EV71 infected HFMD, genotype AG and allele G were risk factors for EV71 infected HFMD. (3) IFNGR2 polymorphism loci rs9808753 was significantly associated with EV71 infection. Genotype AA and allele A were risk factors for EV71 infected HFMD. (4) IL-12RB1 polymorphisms rs3746190, rs12461312, rs17882555, rs1870063, rs2305740, rs2305741 haplotype GCGCAG was a risk factor for EV71 infected HFMD. Haplotype GCGCAG carrier carry a higher risk for EV71 infected HFMD. (5) The alleles of IL-12RB1 polymorphisms rs375947, rs383483, rs391410 and rs401502 might associate with susceptibility to EV71 infected HFMD.IL-12B polymorphism rs2288831, STAT4 gene five SNPs (rs3024866, rs3024891, rs3024900, rs3024903, rs7574865), STAT1 gene seven SNPs (rs11703770, rs2066804, rs2280235, rs397897569, rs45515791, rs7597768, rs77910835) had no association with EV71 infected HFMD.