Association of HLA-DRB1 Alleles with Rheumatic Fever and Rheumatic Heart Disease: A Meta-analysis

ABSTRACT

Background

Rheumatic fever (RF) and its sequel rheumatic heart disease (RHD) is an autoimmune disease caused by an abnormal host immune response to group A streptococcus (GAS) infection. The HLA class II molecules are entailed in immune-mediated infectious, inflammatory, and autoimmune diseases including RHD. However, HLA class II genes are reported to be associated with RF/RHD across different populations with a very little consistency.

Objective

The aim of the study is to investigate the association between HLA class II genes and RF/RHD by meta-analysis.

Methods

A comprehensive literature search was conducted to identify all relevant case-control studies published before December 31, 2019. The data were extracted using standardized form and pooled odds ratio (OR) with 95% confidence interval (CI) are calculated to assess the strength of the association between HLA class II genes and RF/RHD.

Results

Thirteen studies for HLA-DRB1 alleles (1065 patients and 1691 controls) and eight studies for HLA-DQB1 alleles (644 patients and 1088 controls) were finally included. The meta-analysis showed a significantly higher frequency of HLA-DRB1*07 allele (OR = 1.68, P < .0001) in RF/RHD patients when compared to controls, while the frequency of HLA-DRB1*15 allele (OR = 0.60, P = .03) was significantly lower in RF/RHD patients than in controls. However, there were no significant differences in the frequency of HLA-DQB1 alleles between RF/RHD patients and controls.

Conclusions

The results of the meta-analysis suggest that the differential presentation of autoimmune peptides by HLA-DRB1*07 (susceptible) and HLA-DRB1*15 (protective) alleles with different affinities may play a crucial role in the pathogenesis of RF/RHD.

KEYWORDS:

• Rheumatic fever
• rheumatic heart disease
• autoimmunity
• human leukocyte antigen
• HLA-DR
• HLA-DQ
• meta-analysis

Acknowledgments

We acknowledge Department of Health Research, Government of India, for the support of this work under the scheme: Multi Disciplinary Research Unit, Madurai Medical College, Madurai, Tamil Nadu, India.

Author contributions

PM and RT conceived and designed the study. PM and RT carried out literature search and statistical analysis. GR, AR, NG, and KS validated the obtained information and results. PM drafted the manuscript. RT, GR, NG, and KS read and edited the manuscript. AR and MJ critically revised the manuscript. All authors have read and approved the final manuscript.

Compliance with ethical standards

All analyses of the present work were depended on previously published literatures and public databases, there were no human participants included in our study. Thus, this work does not need any ethical approval and patient consent.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Additional information

Funding

This work was supported by the Department of Health Research, Ministry of Health and Family Welfare, Government of India [No.V25011/464/2015/HR].