Major Histocompatibility Complex Class I and Dengue Hemorrhagic Fever: A Meta-Analysis of Human Leukocyte Antigens A*24 and B*44

Abstract

Introduction: Dengue fever (DF) is a disease caused by dengue virus (DENV) from the family Flaviviridae. The role of human leukocyte antigens (HLAs) in dengue fever (DF) and its more severe manifestation, dengue hemorrhagic fever (DHF), has been a topic of great research interest. In addition to HLA profile, race, age, DENV serotype, infection while having certain chronic diseases, and secondary infection are risk factors for DHF susceptibility. Antibody-dependent enhancement (ADE) of dengue virus infection is a mechanism for DHF infection. Individual studies have examined the effects of HLA-A*24 and HLA-B*44 presence on DHF, but none have analyzed these in a meta-analysis. The objective of this study was to determine the effects of HLA-A*24 and HLA-B*44 presence on DHF and DF susceptibility.

Materials and methods: A meta-analysis on DHF and DF susceptibility in patients with HLA-A*24 and HLA-B*44 was conducted. Google Scholar was used to find studies that contained patients with HLA-A*24 or HLA-B*44 that were diagnosed with DHF or DF. Studies containing patients diagnosed using the 1997 WHO guidelines and possessing HLA-A*24 or HLA-B*44 that were diagnosed with DHF or DF, including primary or secondary infection, and studies measuring odds ratios (ORs) were included. Patients diagnosed using the 2009 WHO guidelines and studies in a foreign language, using animals, or lacking odds ratios were excluded. The National Institutes of Health (NIH) quality assessment of the case-control study tool was used, and a Doi plot was generated using MetaXL to assess for risk of bias. Review Manager version 5.4 was used to generate odds ratios and forest plots with subgroup analysis from allele and phenotype frequency data. Ten studies from 2001 to 2015 met the inclusion criteria. The studies included 2837 DHF/DF patients and 4880 healthy control (HC) patients.

Results: HLA-A*24 was associated with a 1.39 times susceptibility to DHF while those possessing HLA-B*44 were 0.62 times susceptible to DHF (OR=1.39 and 95% CI=1.17-1.66; OR=0.62 and 95% CI=0.39-0.99). Neither HLA-A*24 nor HLA-B*44 presence was associated with DF susceptibility (OR=1.04 and 95% CI=0.82-1.33; OR=0.88 and 95% CI=0.68-1.14).

Conclusion: These results indicate that two different major histocompatibility complex (MHC) class I alleles, HLA-A*24 and HLA-B*44, have opposing effects on DHF susceptibility but none on DF susceptibility. The study's specificity is limited in that it examines HLA allele groups and not specific HLA proteins. The results of this study can be used clinically to identify patients that may be at a higher risk of developing DHF based on their HLA profile.

Keywords: dengue fever; dengue hemorrhagic fever; hla-a*24; hla-b*44; mhc class i.

Figure 1. PRISMA 2020 flow diagrams for HLA-A*24 and HLA-B*44 studies

HLA-A*24 is represented on the left, and HLA-B*44 is represented on the right HLA: human leukocyte antigen; PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses

Figure 2. Doi plots for HLA-A*24 and HLA-B*44 in DHF versus HC, DF versus HC, and combined

DF: dengue fever, DHF: dengue hemorrhagic fever, HC: healthy control; HLA: human leukocyte antigen

Figure 3. HLA-A*24 forest plots with subgroup analysis of DF versus healthy control (HC) and DHF versus HC

HLA: human leukocyte antigen; DF: dengue fever; DHF: dengue hemorrhagic fever

Figure 4. HLA-B*44 forest plots with subgroup analysis of DF versus HC and DHF versus HC

HLA: human leukocyte antigen; DF: dengue fever; DHF: dengue hemorrhagic fever; HC: healthy control