Association of Intron 22 inversion and HLA-DRB1*15:01 allele with inhibitor development in hemophilia A: A genetic analysis of risk factors
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Abstract
Background: Inhibitor development in hemophilia A is a major clinical challenge, leading to severe bleeding complications and reduced quality of life. This multifactorial process is influenced by genetic, immunological, and treatmentrelated factors.
Objectives: To determine the association between intron 22 inversion (Inv22) and the HLA-DRB1*15:01 allele with inhibitor development.
Materials and methods: This study investigated inhibitor development during initial and subsequent treatments, assessing the association between Inv22 and HLA-DRB1*15:01 with inhibitor formation in 40 hemophilia A patients, 40 non-hemophilia A patients, and 40 healthy controls.
Results: The study found no significant association between Inv22 or HLADRB1*15:01 allele and inhibitor development during initial (odds ratio (OR): 0.60, 95% CI: 0.11-3.43, p=0.697) or subsequent treatments (OR: 1.33, 95% CI: 0.30-5.93, p=1.000). Similarly, HLA-DRB1*15:01 allele showed no significant correlation (initial: OR: 0.25, 95% CI: 0.06-1.13, p=0.089; subsequent: OR: 0.82, 95% CI: 0.24-2.84, p=1.000). However, patients with both genetic factors had a significantly higher risk of developing inhibitors (OR: 7.90, 95% CI: 1.88-33.06, p=0.007).
Conclusion: This study found no significant association between Inv22 or the HLA-DRB1*15:01 allele and inhibitor development in hemophilia A patients during initial or subsequent treatments. However, their combined presence significantly increased the risk of inhibitor formation, suggesting a potential interactive effect requiring further investigation.
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References
Witmer C, Young G. Factor VIII inhibitors in hemophilia A: etiology and treatment. Ther Adv Hematol. 2013; 4(1): 59-72. doi: 10.1177/2040620712464379.
El-Sheikh A, El-Ghamrawy M, Ibrahim M. Evaluation of factor VIII inhibitors among children with hemophilia A: a single-center study. Zagazig Univ Med J. 2024; 30(8.1): 4104-9. doi: 10.21608/zumj.2023.210924.2821.
Chuansumrit A, Sosothikul D, Rungrungtham T, Sasanakul P, Tapaneeyakorn S, On-Takrai J, et al. The success of the national universal health coverage for hemophilia care in Thailand. Haemophilia. 2021; 27(1): 69-80. doi: 10.1111/hae.14144.
Gouw SC, van den Berg HM, Oldenburg J, Astermark J, de Groot PG, Margaglione M, et al. F8 gene mutation type and inhibitor development in patients with severe hemophilia A: systematic review and meta-analysis. Blood. 2012; 119(12): 2922-34. doi: 10.1182/blood-2011-09-379453.
Oldenburg J, Picard JK, Schwaab R, Brackmann HH, Tuddenham EG, Simpson E. HLA genotype of patients with severe Haemophilia A due to Intron 22 inversion with and without inhibitors of Factor VIII. Thromb Haemost. 1997; 77(2): 238-42. doi: 10.1055/s-0038-1655945
Nathalang O, Sinsiriwong S, Pan-in T, O-charoen R, Chuansumrit A. Association between HLADRB1 alleles and FVIII inhibitors in Thai patients with severe hemophilia A. Turk J Hematol. 2012; 29(1): 34-9. doi: 10.5505/tjh.2012.87126.
Satapornpong P, Jantararoungtong T, Konyoung P, Khunkaew S, Sukasem C. Epidemiology of HLAB*15:02 and other HLA alleles as pharmacogenetic markers in Thais. Front Pharmacol. 2020; 11: 78. doi: 10.3389/fphar.2020.00078.
Astermark J, Oldenburg J, Pavlova A, Berntorp E, Lefvert AK. Polymorphisms in the IL10 and TNFalpha gene promoters and inhibitor development in patients with hemophilia A. Blood. 2006; 107(8): 3167-72. doi: 10.1182/blood-2005-09-3811.
Mancuso ME, Santagostino E. The role of emicizumab in hemophilia A patients with inhibitors. J Thromb Haemost. 2012; 10(5): 781-90. doi: 10.1111/ j.1538-7836.2012.04683.x.
Verbruggen B. Diagnosis and quantification of factor VIII inhibitors. Haemophilia. 2010; 16(102): 20-4. doi: 10.1111/j.1365-2516.2010.02261.x.
Rossetti LC, Radic CP, Larripa IB, De Brasi CD. Genotyping of hemophilia A rearrangements using long-distance PCR. J Thromb Haemost. 2008; 6(5): 830-6. doi: 10.1111/j.1538-7836.2008.02927.x.
Delfan N, Galehdari H, Kazeminejad SR, Alikamali M, Ahmadi M. Analysis of HLA-DRB1*15:01 in multiple sclerosis patients: a case-control study. Zahedan J Res Med Sci. 2017; 19(3): e5647. doi: 10.5812/zjrms.5647.
Pavlova A, Delev D, Lacroix-Desmazes S, Schwaab R, Mende M, Fimmers R, et al. Impact of polymorphisms of the major histocompatibility complex class II on inhibitor development in severe hemophilia A. J Thromb Haemost. 2009; 7(12): 2006-15. doi: 10.1111/j.1538-7836.2009.03636.x.
Abu Arra CM, Arra IA, El-Gharbawy FA, Mansour S. Factor VIII intron 22 inversion in severe hemophilia A patients in Palestine. Scientifica (Cairo). 2020; 2020: 3428648. doi: 10.1155/2020/3428648.
Chuansumrit A, Sasanakul P, Seksarn P, Sosothikul D, Rungrungtham T, Tapaneeyakorn S, et al. Genotype and phenotype of haemophilia A in Thai patients. Haemophilia. 2003; 9(2): 179-86. doi: 10.1046/j.1365-2516.2003.00727.x.
Romphruk AV, Romphruk A, Incheun R, Butthep P, Buaklee N, Jatuasitha S, et al. HLA class I and II alleles and haplotypes in ethnic Northeast Thais. Tissue Antigens. 2010; 75(6): 701-11. doi: 10.1111/j.1399-0039.2010.01449.x.
Abdulqader AMR, Mohammed AI, Rachid S, Ghoraishizadeh P, Mahmood SN. Identification of the intron 22 and intron 1 inversions of the factor VIII gene in Iraqi Kurdish patients with hemophilia A. Clin Appl Thromb Hemost. 2020; 26: 1076029619888293. doi: 10.1177/1076029619888293.
Hay CR, Ollier W, Pepper L, Cumming A, Keeney S, Goodeve AC, et al. HLA class II profile: a weak determinant of factor VIII inhibitor development in severe haemophilia A. Thromb Haemost. 1997; 77(2): 234-7. doi: 10.1055/s-0038-1655944.
