FⅧ Type And Inhibitor Development In Children With Severe Hemophilia A : A Meta-analysis

ObjectiveThe meta-analysis software Rev Man5.4 and Stata16 were used to analyze the incidence of inhibitors in patients with severe hemophilia A with different types of FⅧ(F8)gene mutations,in order to find out F8 related to the production of inhibitors of severe hemophilia in children,and to obtain a more comprehensive risk classification of FⅧ gene mutations and inhibitors.MethodsThe searching words included "haemophilia A","FⅧ deficiency","Gene*","mutation*","inhibitor*"(both in English and Chinese).Pub Med,EMBASE,Web of Science,Cochrane database,Wan Fang Medicine,CNKI and VIP were systematically searched to obtain studies on hemophilia A inhibitor-related gene research in Chinese and English before October 2020.The meta-analysis software Rev Man5.4 and Stata16 were used to statistically process the original data of each study,calculate the combined odds ratio(OR)and 95% confidence interval(CI),and perform sensitivity analyses and risk of publish bias assessment.ResultsA total of 27 studies and 10,402 patients with severe hemophilia A,of which 2053 patients developed inhibitors,and 639 of them were high-titer inhibitors were included in the present study.The types of FⅧ gene mutations included: large fragment deletion,nonsense mutation,22 intron inversion,1 intron inversion,small fragment deletion or insertion,missense mutation,splice site mutation and other unknown mutations.Using22 intron inversion as a reference,the risk of different types of FⅧ gene mutation inhibitors was calculated.The risk of inhibitors in large deletions and nonsense mutations is higher than 22 intron inversions(large deletion OR = 3.3;95% confidence interval [95% CI]:3.14 to 4.93 and nonsense mutation OR = 1.45;95% CI:1.24-1.7),1intron inversion risk is equal(OR = 0.92;95% CI:0.71-1.2),and the risk of splice site mutations,small fragment deletions or insertions,and missense mutations is lower(Slice site mutation OR = 0.48;95% CI: 0.36-0.63,small fragment deletion/insertion OR = 0.34;95% CI:0.29-0.4 and missense mutation OR = 0.34;95% CI:0.29-0.4).Compared with the inversion of intron 22,the combined OR of high-titer inhibitor risk large fragment deletion is 3.05(95% CI:2.33-3.99);nonsense mutation is 1.11(95%CI:0.85-1.18));For 1 intron inversion,OR is 0.62(95% CI:0.36-1.05);For small fragment deletion or insertion,OR is 0.42(95% CI:0.31-0.56);Missense mutation OR is 0.48(95% CI: 0.36-0.63);for splice site mutations,OR is 0.58(95% CI: 0.35-0.97).The relative risk of high-titer inhibitors of different gene mutations is basically similar to the overall risk of inhibitors.ConclusionsLarge deletions and nonsense mutations in FⅧ gene mutations may be important factors for patients with severe hemophilia A,while the risk of inhibitors produced by splice site mutations,small deletions or insertions and missense mutations is low.