Key Genes of the Immune System and Predisposition to Acquired Hemophilia A: Evidence from a Spanish Cohort of 49 Patients Using Next-Generation Sequencing
Abstract
:1. Introduction
2. Results
2.1. Demographic and Clinical Profiles of the AHA Cohort
2.2. Hemostatic Treatment and Immunosuppressive Therapy
2.3. Genetic Analyses and Association Studies
2.3.1. Classical HLA Class I and II Genes
2.3.2. Non-Classical HLA Class I and HLA Class I-like Genes
2.3.3. KIR Genes, Genotypes, and Haplotypes
2.3.4. KLRK1 Gene
3. Discussion
4. Methods
4.1. Patients
4.2. Sample Collection and Phenotype Determinations
4.3. Candidate Region Amplification and Sequencing
4.4. Bioinformatics Analyses
4.5. Reference Samples
4.6. Statistical Analyses
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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A. General Characteristics of the AHA Cohort | ||
Sex, n (%) | Male | 27 (55.1) |
Female | 22 (44.8) | |
Male: female ratio | 1:0.81 | |
Age at diagnosis (years) | Median (IQR) | 74 (59–79) |
Cause of bleeding at onset, n (%) * | Spontaneous | 41 (83.7) |
Surgery | 2 (4.1) | |
Trauma | 3 (6.1) | |
Peripartum | 1 (2.0) | |
ISTH bleeding score * | Median (IQR) | 8 (6–11) |
Males | 8.8 | |
Females | 7.9 | |
Remission status at data capture, n (%) | Complete | 42 (85.7) |
Partial | 6 (12.2) | |
No remission | 1 (2.0) | |
Time to complete remission (days) † | Median (IQR) | 175 (84–266) |
Death at data collection | Overall mortality, n (%) | 13 (26.5) |
AHA specific, n (%) ‡ | 6 (12.2) | |
B. Laboratory Parameters of the AHA Cohort at Diagnosis | ||
Hemoglobin (g/dL) | Median (IQR) | 6.8 (6.0–8.5) |
aPTT (s) § | Median (IQR) | 76 (62–90.8) |
FVIII:C (%) | Median (IQR) | 1 (0.3–3.6) |
FVIII level category, n (%) | Severe (≤1%) | 28 (57.1) |
Moderate (>1 to ≤5%) | 12 (24.5) | |
Mild (>6 to ≤50%) | 9 (18.4) | |
Inhibitor titer (BU/mL) | Median (IQR) | 18 (5–62) |
Inhibitor titer category, n (%) | 0 to ≤10 BU/mL | 19 (38.8) |
>10 to ≤100 BU/mL | 22 (44.9) | |
>100 to ≤1000 BU/mL | 8 (16.3) | |
Inhibitor kinetics type, n (%) | Type I | 23 (46.9) |
Type II | 26 (53.1) |
Allele | Allele Count in AHA Cohort | Allele Freq (%) in AHA Cohort | Allele Count in Reference Sample * | Allele Freq (%) in Reference Sample * | Fisher p-Value | Odds Ratio (95% CI) |
---|---|---|---|---|---|---|
A*03:01 | 3 | 3.06 | 22 | 11.00 | 0.024 | 0.26 (0.06–0.85) |
DRB1*13:03 | 7 | 7.14 | 2 | 1.00 | 6.82 × 103 | 7.56 (1.64–51.40) |
Rs1049174 Genotype | Haplotype | Count in AHA Cohort | Freq (%) in AHA Cohort | Count in IBS * | Freq (%) in IBS * | Fisher p-Value | Odds Ratio (95% CI) | Fisher p-Value for Global Association |
---|---|---|---|---|---|---|---|---|
CC | HNK/HNK | 0 | 0.00 | 10 | 9.35 | 0.031 | 0 (0–0.89) | 0.012 |
CG | HNK/LNK | 29 | 59.18 | 42 | 39.25 | 0.024 | 2.23 (1.09–4.58) | |
GG | LNK/LNK | 20 | 40.82 | 55 | 51.40 | 0.232 | 0.65 (0.32–1.34) |
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Pardos-Gea, J.; Martin-Fernandez, L.; Closa, L.; Ferrero, A.; Marzo, C.; Rubio-Rivas, M.; Mitjavila, F.; González-Porras, J.R.; Bastida, J.M.; Mateo, J.; et al. Key Genes of the Immune System and Predisposition to Acquired Hemophilia A: Evidence from a Spanish Cohort of 49 Patients Using Next-Generation Sequencing. Int. J. Mol. Sci. 2023, 24, 16372. https://doi.org/10.3390/ijms242216372
Pardos-Gea J, Martin-Fernandez L, Closa L, Ferrero A, Marzo C, Rubio-Rivas M, Mitjavila F, González-Porras JR, Bastida JM, Mateo J, et al. Key Genes of the Immune System and Predisposition to Acquired Hemophilia A: Evidence from a Spanish Cohort of 49 Patients Using Next-Generation Sequencing. International Journal of Molecular Sciences. 2023; 24(22):16372. https://doi.org/10.3390/ijms242216372
Chicago/Turabian StylePardos-Gea, Jose, Laura Martin-Fernandez, Laia Closa, Ainara Ferrero, Cristina Marzo, Manuel Rubio-Rivas, Francesca Mitjavila, José Ramón González-Porras, José María Bastida, José Mateo, and et al. 2023. "Key Genes of the Immune System and Predisposition to Acquired Hemophilia A: Evidence from a Spanish Cohort of 49 Patients Using Next-Generation Sequencing" International Journal of Molecular Sciences 24, no. 22: 16372. https://doi.org/10.3390/ijms242216372