Cumulative Genetic Score To Predict Response To Intravenous Immunoglobulin In Children With Kawasaki Disease

OBJECTIVE:To determine the multiple single nucleotide polymorphisms(SNPs)in predicting IVIG(Intravenous Immunoglobulin)responsiveness,risk-associated SNPs were compared in children with Kawasaki Disease(KD)in North China.METHODS:1.From June 2009 to October 2017,children diagnosed with KD and treated with IVIG(2g/kg)in children's hospital Capital Institute of Pediatrics,Beijing,China were recruited.2.KD patients were classified into response group and nonresponse group depending on the responsiveness to IVIG therapy.3.Previously reported SNPs associated with IVIG nonresponse were detected by polymerase chain reaction(PCR)and TaqMan probe detection.4.SNPs differences between response and nonresponse groups were statistically analyzed by FISHER' s exact test(SPSS 20.0).Linkage disequilibrium and Hardy-Weinberg equilibrium were detected among SNPs with HAPLOVIEW.Multivariate logistic regression with backward selection were performed to export SNPs related with IVIG response(SPSS 20.0).The above related SNPs were used to make prognostic nomogram that could give each SNP different score.To assess IVIG response predictability of prognostic nomogram,we calculated the area under the receiver-operating characteristic(ROC)curve(AUC),sensitivity,and specificity,respectively.RESULTS:1.161 KD patients were enrolled in this study,including 51 IVIG nonresponders and 110 IVIG responders.In nonresponse group,the ratio of male to female is 9.4 to 1 and average age is 2.13 ± 1.58 years.In response group,the proportion is 6.36 to 1 and mean age is 2.13 ± 1.58 years.2.The 18 SNPs possibly associated with nonresponse to IVIG reported,as the objective of this study,were selected by reviewing of the literature via the PUBMED website(https://www.ncbi.nlm.nih.gov/)and obtained literature.3.No significant association was observed between the IVIG response group and IVIG nonresponse group with 18 SNPs by Fisher's exact test(P<0.05).4.Linkage disequilibrium shows that rs396991 is correlated with rs3219018 and rs180127 is correlated with rs3219018 in FCGR gene,rs16944 is completely correlated with rs1143627 in IL-1B gene,rs10056474 is correlated with rs746994 in SMAD5 gene.5.rsl6944,rs76863441,rs10056474,rs746994,rs113420705 and rs28493229 are significant predictors to IVIG response by multivariate logistic regression with backward selection(P 0.011).6.The prognostic nomogram that integrated above 6 SNPs as factors for IVIG response is made to predict probability of IVIG response in each patient.We calculated AUC according to total scores in response and nonresponse groups which is 0.702.When the KD patient' s total scores is 18.25,sensitivity of IVIG response is 53.6%and specificity of IVIG response is 80.4%.Conclusions:Combining rs16944 locus of IL-1B,rs 10056474 and rs746994 loci of SMAD5 and rs28493229 of ITPKC with rs113420705 of CASPASE3 can predict response to IVIG therapy in children with KD and guide clinicians to choose individualized initial treatment to reduce and prevent coronary complications.