The polygenic nature of inhibitors in hemophilia A: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort

Astermark, Jan; Donfield, Sharyne; Gomperts, Edward D.; Schwarz, J. M.; Menius, Erika; Pavlova, Anna; Oldenburg, Johannes; Kessing, Bailey; DiMichele, Donna; Shapiro, Amy D.; Winkler, Cheryl A.; Berntorp, Erik

doi:10.1182/blood-2012-06-434803

Cited by 96 publications

(75 citation statements)

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“…Allele and genotype frequencies were similar to those previously described. 31 No significant association between the genotypes or the individual allele frequencies, and the development of inhibitors was observed, in agreement with a recently published genome-wide association study by Astermark et al 32 (Online Supplementary Table S1; P>0.05).…”

Section: Single Nucleotide Polymorphismssupporting

confidence: 79%

“…The authors identified 53 single nucleotide polymorphisms as significant predictors of inhibitor status, thus highlighting the complexity of the anti-FVIII immune response. 32 However, the genome-wide association study did not find associations of single nucleotide polymor-HMOX1 promoter polymorphism and FVIII inhibitors haematologica | 2013; 98 (10) 1653 Table 2. HO-1 (GT) n microsatellite distribution in patients with hemophilia A. phisms located in the promoter of the HMOX1 gene with the inhibitor status of the patients, which is in agreement with the present study.…”

Section: Discussionmentioning

confidence: 99%

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Development of inhibitory antibodies to therapeutic factor VIII in severe hemophilia A is associated with microsatellite polymorphisms in the HMOX1 promoter

et al. 2013

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Induction of heme oxygenase-1, a stress-inducible enzyme with anti-inflammatory activity, reduces the immunogenicity of therapeutic factor VIII in experimental hemophilia A. In humans, heme oxygenase-1 expression is modulated by polymorphisms in the promoter of the heme oxygenase-1-encoding gene (HMOX1). We investigated the relationship between polymorphisms in the HMOX1 promoter and factor VIII inhibitor development in severe hemophilia A. We performed a case-control study on 99 inhibitor-positive patients and 263 patients who did not develop inhibitors within the first 150 cumulative days of exposure to therapeutic factor VIII. Direct sequencing and DNA fragment analysis were used to study (GT) n polymorphism and single nucleotide polymorphisms located at -1135 and -413 in the promoter of HMOX1. We assessed associations between the individual allele frequencies or genotypes, and inhibitor development. Our results demonstrate that inhibitor-positive patients had a higher frequency of alleles with large (GT) n repeats (L: n≥30), which are associated with lesser heme oxygenase-1 expression (odds ratio 2.31; 95% confidence interval 1. 46-3.66; P<0.001]. Six genotypes (L/L, L/M, L/S, M/M, M/S and S/S) of (GT) n repeats were identified (S: n<21; M: 21≤n<30). The genotype group including L alleles (L/L, L/M and L/S) was statistically more frequent among inhibitor-positive than inhibitor-negative patients, as compared to the other genotypes (33.3% versus 17.1%) (odds ratio 2.21, 95% confidence interval 1.30-3.76; P<0.01). To our knowledge, this is the first association identified between HMOX1 promoter polymorphism and development of anti-drug antibodies. Our study paves the way towards modulation of the endogenous anti-inflammatory machinery of hemophilia patients to reduce the risk of inhibitor development Development of inhibitory antibodies to therapeutic factor VIII in severe hemophilia A is associated with microsatellite polymorphisms in the HMOX1 promoter

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Section: Single Nucleotide Polymorphismssupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Development of inhibitory antibodies to therapeutic factor VIII in severe hemophilia A is associated with microsatellite polymorphisms in the HMOX1 promoter

et al. 2013

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“…This study highlighted the complexity of the genetic polymorphisms that might modulate antibody responses against FVIII and FIX. 40 …”

Section: Fviii Haplotypesmentioning

confidence: 99%

Risky business of inhibitors: HLA haplotypes, gene polymorphisms, and immune responses

Reipert

2014

Hematology

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The development of neutralizing antibodies against factor VIII (FVIII inhibitors) and factor IX (FIX inhibitors) is the major complication in hemophilia care today. The antibodies neutralize the biological activity of FVIII and FIX and render replacement therapies ineffective. Antibodies are generated as a result of a cascade of tightly regulated interactions between different cells of the innate and the adaptive immune system located in distinct compartments. Any event that modulates the repertoire of specific B or T cells, the activation state of the innate and adaptive immune system, or the migration pattern of immune cells will therefore potentially influence the risk for patients to develop inhibitors. This chapter reviews our current understanding of different pathways of antibody development that result in different qualities of antibodies. Potential differences in differentiation pathways leading to high-affinity neutralizing or low-affinity non-neutralizing antibodies and the potential influence of gene polymorphisms such as HLA haplotype, FVIII haplotype, and polymorphisms of immunoregulatory genes are discussed. Learning Objectives• To understand that FVIII and FIX inhibitors are only the tip of the iceberg: antibodies are generated as a result of a cascade of tightly regulated interactions between different cells of the innate and the adaptive immune system located in distinct compartments • To understand that any event that affects the activation state of the innate or the adaptive immune system, the repertoire of specific B or T cells, or the migration pattern of immune cells potentially influences the risk for patients to develop FVIII or FIX inhibitors Neutralizing antibodies against FVIII and FIX are the major challenge in replacement therapies for patients with hemophiliaThe development of neutralizing antibodies against factor VIII (FVIII inhibitors) and factor IX (FIX inhibitors) is the major complication in hemophilia care today. The antibodies neutralize the biological activity of FVIII and FIX and render replacement therapies ineffective. FVIII inhibitors develop in ϳ20%-32% of patients with severe hemophilia A (plasma FVIII activities Ͻ1%) and in ϳ3%-13% of patients with moderate (plasma FVIII activity 1%-5%) and mild (plasma FVIII activity 5%-25%) hemophilia A. 1,2 Recently, Eckardt et al 3 reported that the risk for patients with mild and moderate hemophilia A to form inhibitors increases with an increasing number of days of exposure to FVIII products and might be higher than anticipated.Most FVIII inhibitors bind to functionally important domains of FVIII and prevent its interaction with other coagulation factors such as factors IIa, IXa, and X and VWF or with phospholipids. 4 Other FVIII inhibitors have catalytic activities and hydrolyze the protein. 4 FIX inhibitors are seen less frequently than FVIII inhibitors. Their overall incidence is 1%-3% for all patients with hemophilia B treated with FIX products and 9%-23% for patients with severe hemophilia B who express plasma FIX activit...

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“…Polymorphisms in other immune related gene such as CTLA-4, DOCK2, MAPK9, PTPRR and CD36 gene have also been linked to inhibitor development [41,42]. In a recent study by Astermark (2013), 53 SNPswere reported to be the predictors of inhibitor status, further indicating the complexity of immune response and immune modifier genes in the development inhibitors [43].…”

Section: Hla and Immune Related Genes In Inhibitor Productionmentioning

confidence: 99%

Violating the Theory of Single Gene-Single Disorder: Inhibitor Development in Hemophilia

AlFadhli

Nizam

2014

Indian J Hematol Blood Transfus

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The polygenic nature of inhibitors in hemophilia A: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort

Abstract: Key Points• The data demonstrate the complexity of the genetic contribution to inhibitor development in people with hemophilia A.• Potentially decisive markers have been identified, indicating the importance of further evaluation of intracellular signaling pathways.

Cited by 96 publications

References 47 publications

Development of inhibitory antibodies to therapeutic factor VIII in severe hemophilia A is associated with microsatellite polymorphisms in the HMOX1 promoter

Development of inhibitory antibodies to therapeutic factor VIII in severe hemophilia A is associated with microsatellite polymorphisms in the HMOX1 promoter

Risky business of inhibitors: HLA haplotypes, gene polymorphisms, and immune responses

Violating the Theory of Single Gene-Single Disorder: Inhibitor Development in Hemophilia

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