Talks
Academic/Professional Position (Other)
MS4
Presentation Type
Oral Presentation
Discipline Track
Biomedical Science
Abstract Type
Research/Clinical
Abstract
Background: Hemophilia-A (HA) is caused by factor VIII (FVIII)-gene (F8) mutations, variably deficient plasma FVIII activity (FVIII:C), and reduced to absent intrinsic-pathway amplification of coagulation. Infused therapeutic-FVIII-proteins (tFVIIIs) prevent bleeding in all HA patients (HAPs) but about 25-30% with severe-HA and 5-10% with non-severe-HA become refractory with the development of neutralizing-tFVIII-antibodies (“FVIII-inhibitors (FEIs)”). We use Immunochip genotyping in the PATH Study to screen the MHC-class-II (MHCII)-region for classical- and non-classical-HLA-class-II (HLAII)-genes and -pseudogenes for association with FEI-risk while accounting for the non-independence of data due to genetic relatedness and F8 mutational heterogeneity using novel statistical methods. Our results establish that HLAII DQ-allotypes influence the risk of FEI development in HAPs.
Methods: The FEI-status of 438 North American HAPs—200 with black-African-ancestry and 238 with white-European-ancestry—was the dependent-variable of interest. The F8-mutation data and a genetic-relatedness matrix were incorporated into a binary-linear-mixed model of genetic-association with FEI-status (Yes vs. No), with ‘Yes’ designating those HAPs having FEIs of either any titer (i.e., >0.4 Bethesda Units (BUs) mL-1) or only high-titer (i.e., ³5.0 BUs mL-1). We used the ImmunoChip to conduct an MHCII-region-wide association screen of FEI-risk against the set of 926 distinct single-nucleotide-variations (SNVs) with high-quality genotypes that passed QC.
Results: Following the analytical procedure used in prior studies designed to identify determinants of FEI-risk, we performed the extended-MHCII-region-wide association screen on two groups of FEI-positive HAPs, those with any titer or those with only high-titer. HAPs in the high-titer FEI group are suspected to be more homogeneous with respect to the underlying immunobiology as they appear clinically to have induced full adaptive immunity. In contrast, HAPs in the any titer group are heterogenous as some will have transient FEIs that spontaneously disappear, and others will have FEIs that may remain low-titer despite continued FVIII-replacement-therapy.
We found several SNPs that were not only significantly associated in both FEI groups—or significant and suggestive respectively in the high-titer and any titer groups—but also increased in significance (i.e., their p-values decreased) under the high-titer analysis (see Figure). The latter observation indicates that these significant results correspond to true associations that became more apparent as sources of “noise” were removed upon going from the any titer to high-titer analysis. These included a SNP in the 3’-untranslated-region (UTR) of DQB1 (rs1049225, p-value=5.7E-7) and two intergenic HLAII region SNPs (rs2647012, p-value=1.1E-5; and rs2858324, p-value=1.1E-5). The DQB1 SNP reached an ImmunoChip-wide significance threshold in the high-titer analysis (i.e., a p-value < 5.9E-7) and extended-MHCII-region-wide significance in the any titer analysis (i.e., p-value < 5.4E-5). Although the two HLAII-intergenic SNPs were not ImmunoChip-wide significant, they were significant across the extended-MHCII-region (i.e., p-value < 5.4E-5). We found two SNPs that were significant and suggestive respectively in the high-titer and any titer FEI analyses (rs9276189, p-value=1.3E-5; and rs2856717, p-value=3.3E-5) as well as one SNP that was significant in the high-titer FEI analyses but not significant or suggestive in the any titer analysis (rs9271366, p-value=1.9E-6).
Conclusion: Our results establish that a novel DQB1 genetic variant is associated with FEIs.
Recommended Citation
Bouls, Ruayda; Ibarra, Paola; Almeida, Marcio; Diego, Vincent P.; Curran, Joanne E.; Peralta, Juan M.; Kumar, Satish; Blangero, John; Williams-Blangero, Sarah; and Howard, Tom E., "Results from an Association-Scan of the Extended MHC-class-II Region Using Novel Association-Based Statistical Methods Establish that DQ Allotypes Influence the Risk of FVIII Inhibitor Development in Hemophilia-A Patients" (2024). Research Symposium. 18.
https://scholarworks.utrgv.edu/somrs/2023/talks/18
Included in
Results from an Association-Scan of the Extended MHC-class-II Region Using Novel Association-Based Statistical Methods Establish that DQ Allotypes Influence the Risk of FVIII Inhibitor Development in Hemophilia-A Patients
Background: Hemophilia-A (HA) is caused by factor VIII (FVIII)-gene (F8) mutations, variably deficient plasma FVIII activity (FVIII:C), and reduced to absent intrinsic-pathway amplification of coagulation. Infused therapeutic-FVIII-proteins (tFVIIIs) prevent bleeding in all HA patients (HAPs) but about 25-30% with severe-HA and 5-10% with non-severe-HA become refractory with the development of neutralizing-tFVIII-antibodies (“FVIII-inhibitors (FEIs)”). We use Immunochip genotyping in the PATH Study to screen the MHC-class-II (MHCII)-region for classical- and non-classical-HLA-class-II (HLAII)-genes and -pseudogenes for association with FEI-risk while accounting for the non-independence of data due to genetic relatedness and F8 mutational heterogeneity using novel statistical methods. Our results establish that HLAII DQ-allotypes influence the risk of FEI development in HAPs.
Methods: The FEI-status of 438 North American HAPs—200 with black-African-ancestry and 238 with white-European-ancestry—was the dependent-variable of interest. The F8-mutation data and a genetic-relatedness matrix were incorporated into a binary-linear-mixed model of genetic-association with FEI-status (Yes vs. No), with ‘Yes’ designating those HAPs having FEIs of either any titer (i.e., >0.4 Bethesda Units (BUs) mL-1) or only high-titer (i.e., ³5.0 BUs mL-1). We used the ImmunoChip to conduct an MHCII-region-wide association screen of FEI-risk against the set of 926 distinct single-nucleotide-variations (SNVs) with high-quality genotypes that passed QC.
Results: Following the analytical procedure used in prior studies designed to identify determinants of FEI-risk, we performed the extended-MHCII-region-wide association screen on two groups of FEI-positive HAPs, those with any titer or those with only high-titer. HAPs in the high-titer FEI group are suspected to be more homogeneous with respect to the underlying immunobiology as they appear clinically to have induced full adaptive immunity. In contrast, HAPs in the any titer group are heterogenous as some will have transient FEIs that spontaneously disappear, and others will have FEIs that may remain low-titer despite continued FVIII-replacement-therapy.
We found several SNPs that were not only significantly associated in both FEI groups—or significant and suggestive respectively in the high-titer and any titer groups—but also increased in significance (i.e., their p-values decreased) under the high-titer analysis (see Figure). The latter observation indicates that these significant results correspond to true associations that became more apparent as sources of “noise” were removed upon going from the any titer to high-titer analysis. These included a SNP in the 3’-untranslated-region (UTR) of DQB1 (rs1049225, p-value=5.7E-7) and two intergenic HLAII region SNPs (rs2647012, p-value=1.1E-5; and rs2858324, p-value=1.1E-5). The DQB1 SNP reached an ImmunoChip-wide significance threshold in the high-titer analysis (i.e., a p-value < 5.9E-7) and extended-MHCII-region-wide significance in the any titer analysis (i.e., p-value < 5.4E-5). Although the two HLAII-intergenic SNPs were not ImmunoChip-wide significant, they were significant across the extended-MHCII-region (i.e., p-value < 5.4E-5). We found two SNPs that were significant and suggestive respectively in the high-titer and any titer FEI analyses (rs9276189, p-value=1.3E-5; and rs2856717, p-value=3.3E-5) as well as one SNP that was significant in the high-titer FEI analyses but not significant or suggestive in the any titer analysis (rs9271366, p-value=1.9E-6).
Conclusion: Our results establish that a novel DQB1 genetic variant is associated with FEIs.