Investigating Genetic Predictors of Inhibitors among Persons with Hemophilia Open Access
Payne, Amanda (Spring 2018)
Abstract
Hemophilia A (HA), an inherited bleeding disorder affecting approximately 20,000 males in the United States, is caused by pathogenic variants in the F8 gene leading to loss or reduced functionality of the procoagulant factor VIII (FVIII). HA is most-commonly treated by replacing the missing or dysfunctional FVIII. Unfortunately, 10%-15% of persons with HA develop antibodies (inhibitors) to the replacement FVIII, rendering it ineffective. Identifying persons at highest risk of developing inhibitors is important, as treatment may be altered. A previously-validated inhibitor-risk-prediction tool has limitations, including its reliance on prior hemophilia treatment and knowledge of family history. An inhibitor-risk-prediction tool that relies on information available at the time of HA diagnosis could be more useful clinically. Risk factors for inhibitors include situations that make recognition of foreign FVIII and upregulation of the immune system more likely. Family studies have indicated a genetic component to inhibitor risk. This dissertation explores the feasibility of constructing an inhibitor-risk-prediction tool that uses only genetic information.
In Aim 1 information about the hemophilia genotype was used to predict inhibitor status. Three different paradigms to categorize hemophilia genotype were constructed, and the ability of each to predict inhibitor status was evaluated. The tool that used previously-published estimates of hemophilia genotype effect performed best; however, none of the tools performed as well as the previously-validated tool.
In Aim 2 variation in immune response genes was used to predict inhibitor status. Estimates for the effect size of genetic variants were obtained in two ways: a meta-analysis was performed on published studies, and estimates were empirically derived from a genetic association study. Two tools were then developed, using estimates from the meta-analysis or the empirically-derived data. Neither of the tools performed as well as the previously-validated tool.
Aim 3 combined information from aims 1 and 2, using both hemophilia genotype and variation in immune response genes. The best-performing tool performed similarly to the previously-validated tool, without requiring treatment or family history information.
The results of this investigation indicate that prediction of inhibitors using only genetic information may be possible. Further validation of the results in an external population is warranted.
Table of Contents
Chapter 1: Introduction and Rationale 1
Chapter 2: Background 4
Hemophilia A 4
Inhibitors in Hemophilia A 4
Impact of Inhibitors 5
How Inhibitors Develop 5
Risk Factors for Inhibitor Development 6
Non-Genetic Risk Factors 6
Genetic Risk Factors 7
Hemophilia Genotype 7
Immune Response Genetics 9
Race/Ethnicity 10
Predicting Inhibitor Risk 10
Dissertation Aims 12
Chapter 3: Evaluation of variant-scoring tools for use in assigning inhibitor risk among persons with hemophilia A 14
Abstract 14
Introduction 15
Methods 17
Population 17
Genotyping 18
Risk Prediction Tools 18
Tool based on predicted pathogenicity (Pathogenicity Tool) 18
Tool based on predicted impact on gene function (Function Tool) 18
Tool based on prior evidence (Evidence-Based Tool) 19
Statistical Analysis 20
Results 20
Pathogenicity Tool 20
Function Tool 20
Evidence-based Tool 21
Discussion 21
Conclusions 23
Acknowledgements 24
Tables 25
Figures 26
Chapter 4: Genetic variants associated with inhibitors among persons with hemophilia: A systematic review and meta-analysis 29
Abstract 29
Introduction 30
Methods 31
Results 33
Study identification and selection 33
Study characteristics 33
Variants investigated 34
Summary estimates of effect 34
T cell regulators 34
Class I HLA genes 35
Class II HLA genes 35
Cytokines 36
Evaluation of heterogeneity 36
Evaluation of bias 36
Publication bias 37
Study-related bias 37
Discussion 37
Conclusions 40
Acknowledgements 41
Tables 42
Figures 48
Chapter 5: Associations between variants in immune response genes and inhibitors among persons with hemophilia A 51
Abstract 51
Introduction 52
Methods 53
Population 53
Laboratory Methods 54
Statistical Analysis 55
Results 56
HLA Class I and II Variants 56
Other Variants 57
Discussion 58
Conclusions 61
Acknowledgements 61
Tables 62
Chapter 6: Evaluation of inhibitor risk prediction tools based on genetic risk factors in persons with hemophilia A 68
Abstract 68
Introduction 69
Methods 70
Population 70
Genotyping 70
Risk Prediction Tools 71
Hemophilia Genotype Scoring 71
Immune Response Variant Scoring 72
Statistics 73
Results 73
Discussion 75
Conclusions 77
Tables 78
Figures 80
Chapter 7: Summary, strengths, limitations, public health implications, and future research 86
Summary 86
Strengths 88
Limitations 89
Public Health Implications 89
Future Research 90
References 92
Supplementary Information 113
Chapter 3 113
Chapter 4 114
Chapter 5 199
Chapter 6 211
About this Dissertation
| School | |
|---|---|
| Department | |
| Degree | |
| Submission | |
| Language |
|
| Research Field | |
| Keyword | |
| Committee Chair / Thesis Advisor | |
| Committee Members |
Primary PDF
| Thumbnail | Title | Date Uploaded | Actions |
|---|---|---|---|
|
|
Investigating Genetic Predictors of Inhibitors among Persons with Hemophilia () | 2018-04-02 13:15:36 -0400 |
|
Supplemental Files
| Thumbnail | Title | Date Uploaded | Actions |
|---|