Whole-exome sequencing to identify genetic risk variants underlying inhibitor development in severe hemophilia A patients

Gorski, Marcin M.; Blighe, Kevin; Lotta, Luca A.; Pappalardo, Emanuela; Garagiola, Isabella; Mancini, Ilaria; Mancuso, Maria Elisa; Fasulo, Maria Rosaria; Santagostino, Elena; Peyvandi, Flora

doi:10.1182/blood-2015-12-685735

Cited by 34 publications

(26 citation statements)

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“…The residual amount of endogenous FVIII offers a likely explanation for this difference, through the induction of natural immune tolerance . Furthermore, established determinants of inhibitor formation are the patient's genetic background, and environmental factors . Among them, the type of mutation in F8 is the strongest risk factor for inhibitor development .…”

Section: Introductionsupporting

confidence: 86%

Prediction of factor VIII inhibitor development in the SIPPET cohort by mutational analysis and factor VIII antigen measurement

Spena

Garagiola

Cannavó

et al. 2018

Journal of Thrombosis and Haemostasis

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Background The type of F8 mutation is the main predictor of inhibitor development in patients with severe hemophilia A. Mutations expected to allow residual synthesis of factor VIII are likely to play a protective role against alloantibody development by inducing immune tolerance. According to the expected full or partial impairment of FVIII synthesis, F8 variants are commonly classified as null and non-null. Objectives To explore the mutation type-inhibitor risk association in a cohort of 231 patients with severe hemophilia A enrolled in the Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET) randomized trial. Methods The genetic defects in these patients, consisting of inversions of intron 22 (n = 110) and intron 1 (n = 6), large deletions (n = 16), and nonsense (n = 38), frameshift (n = 28), missense (n = 19) and splicing (n = 14) variants, of which 34 have been previously unreported, were reclassified according to two additional criteria: the functional effects of missense and splicing alterations as predicted by multiple in silico analyses, and the levels of FVIII antigen in patient plasma. Results A two-fold increase in inhibitor development for in silico null mutations as compared with in silico non-null mutations (hazard ratio [HR] 2.08, 95% confidence interval [CI] 0.84-5.17) and a 3.5-fold increase in inhibitor development for antigen-negative mutations as compared with antigen-positive mutations (HR 3.61, 95% CI 0.89-14.74] were found. Conclusions Our findings confirm an association between the synthesis of minute amounts of FVIII and inhibitor protection, and underline the importance of investigating the residual FVIII antigen levels associated with causative variants in order to understand their clinical relevance.

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Section: Introductionsupporting

confidence: 86%

Prediction of factor VIII inhibitor development in the SIPPET cohort by mutational analysis and factor VIII antigen measurement

Spena

Garagiola

Cannavó

et al. 2018

Journal of Thrombosis and Haemostasis

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“…这些因素可能造成部分HA患者在接触FⅧ制品前血浆中就含有抗FⅧ非中和抗体, 这部分携带抗体的患者将来替代治疗过程中更容易出现抑制物 [40] . 此外, 关于携带抑制物患者全外显子组测序研究结果发现多个免疫调节相关分子的有害突变及LCT基因 http://engine.scichina.com/doi/10.1360/N052017-00271 rs3754689的错义突变易导致抑制物的产生 [41] . 非遗传因素包括外伤史、暴露日、输注剂量和药物品种及治疗策略等.…”

Section: 研究表明患者抑制物发生的危险因素包括遗传unclassified

Research progress of hereditary blood diseases

Li¹,

Yang²

2017

Sci. Sin.-Vitae

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Applications of proteomics in hepatic diseases research Science in China Series C-Life Sciences 47, 101 (2004); Roles and mechanisms of ginsenoside in cardiovascular diseases: progress and perspectives SCIENCE CHINA Life Sciences 59, 292 (2016); Advances in research into gamete and embryo-fetal origins of adult diseases SCIENCE CHINA Life Sciences 62, 360 (2019); Platelet proteomics and its advanced application for research of blood stasis syndrome and activated blood circulation herbs of Chinese medicine

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“…The study found that individuals bearing the CGG or TGG haplotypes are 5.82 times more likely to develop inhibitors, whereas the CGG or TAT haplotypes appear to confer protection because they are more frequent in the group of patients without inhibitors (Chaves et al, 2010a). A genome-wide association study (GWAS) showed a protective role for the missense variant rs3754689 (C_000002.11:g.136590746C>T) in the lactase LCT gene (Gorski et al, 2016). The role of the LCT gene (i.e., hypolactasia) in the immune response remains unclear.…”

Section: Introductionmentioning

confidence: 99%

A Differentially Methylated CpG Site in theIL4Gene Associated with Anti-FVIII Inhibitor Antibody Development in Hemophilia A

Souza

Ferreira

et al. 2019

Preprint

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40Hemophilia A is the most common clotting disorder in humans. It affects one in five 41 thousand live-born children. Mutations in the X-chromosome linked F8 gene lead to the 42 deficiency of circulating factor VIII (FVIII). The defect is characterized by severe 43 bleeding. The standard therapy is to replace the deficient factor intravenously. The main 44 adverse event of the therapy is the development of anti-FVIII inhibitor antibodies that 45 impair coagulation and result in increased complications and risk of death. Several risk 46 factors have been described for the development of inhibitor antibodies, among them 47 age, type of FVIII administered, ethnicity, and variant alleles in immune response 48 genes. Epigenetic risks factors have not yet been explored. This work aimed to evaluate 49 2 the methylation statuses at thirteen CpG sites (5meCpG) in regulatory regions of the 50 IL1B, IL2, IL4, IL6, IL10, TNF, IFNG, CTLA4, CD28, and CST7 immune regulation 51 genes in hemophilia A affected males on replacement therapy who develop or do not 52 develop inhibitor antibodies. At each of the thirteen specific CpG sites, we observed one 53 of three possible statuses: hypermethylated, hypomethylated or intermediate 54 methylated. We found a statistically significant (p = 0.04) decrease in the methylation 55 level at one CpG site in the IL4 intron 1 (CpG-3) in the affected group of patients 56 presenting with anti-FVIII inhibitors as compared with the group of patients without 57 inhibitors. The differential 5meCpG-3 maps within a predicted enhancer region in IL4 58 intron 1 that overlaps DNase I hypersensitive chromatin region of the Th2 IL5, IL13, 59 and IL4 cytokine gene cluster and, therefore, permissive for gene expression. Six-bp 60 upstream of the differentially 5meCpG-3 is the rs2227282 cis expression quantitative 61 trait locus that influences the transcript levels of the PDLIM4, SLC22A4, SLC22A5, 62 RAD50, IL4, KIF3A, SEPT8 genes. We consider the IL4 (CpG-3) site a promising lead 63 epigenetic mark, the potential value of which must be appraised in a larger group of 64 patients. The methodology employed also allowed to evaluate the distribution of the IL6 65 rs35081782 insertion/deletion variant, associated with white blood cell count traits in 66 genome-wide association studies, and which showed no difference in distribution 67 between the groups of patients. 68 69 90 91Risk factors for inhibitor development are classified into non-genetic and genetic. 92Among non-genetic risks, the age at the replacement therapy, the type of hemorrhage 93 and the factor administered have been described (Ragni et al., 2009). Among the genetic 94 risk factors, the most well-described factor is the type of causative mutation. Mutations 95 that associate with a higher risk of developing inhibitors are linked to significant 96 functional alterations or complete absence of FVIII. About 40% of patients with large 97 deletions develop inhibitors, while nonsense mutations account for up to 30% of 98

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Whole-exome sequencing to identify genetic risk variants underlying inhibitor development in severe hemophilia A patients

Cited by 34 publications

References 51 publications

Prediction of factor VIII inhibitor development in the SIPPET cohort by mutational analysis and factor VIII antigen measurement

Prediction of factor VIII inhibitor development in the SIPPET cohort by mutational analysis and factor VIII antigen measurement

Research progress of hereditary blood diseases

A Differentially Methylated CpG Site in theIL4Gene Associated with Anti-FVIII Inhibitor Antibody Development in Hemophilia A

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