Rheumatic Heart Disease in Uganda: The Association between MHC Class II HLA DRB1 Alleles and Disease: A Case Control Study

Background: Rheumatic heart disease remains a leading cause of morbidity and mortality among young adults in Uganda. Genetic susceptibility through the major histocompatibility class II human leucocyte antigens has been strongly associated with RHD. In Uganda and much of sub Saharan Africa there is lack of data on genetic susceptibility to RHD. Objective: The objective of this study was to compare the frequency of HLA class II DR alleles between RHD cases and normal controls, and to determine the strength of association with RHD. Methods: One hundred ninety-nine (199) participants, 96 established RHD cases aged 5-60 years and 103 age and sex matched normal controls were recruited into the study. DNA was manually extracted from buffy coat samples and HLA analysis carried out using the Olerrup low resolution SSP kits. Allelic frequencies of genes from the HLA-DR locus from study participants were stratified by study groups (cases and controls) and the strength of association was estimated using odds ratios (OR) with 95% confidence intervals (CI) from conditional logistic regression. P values were corrected for multiple hypothesis testing. Results: 199 participants (103 female, 51.8%) completed the study. Matching was successful with the ratio of male to female participants in each group being 1:1. The mean (SD) and median (IQR) age in years for cases and controls were 29.6 (10.2) and 29(18), and 29.8(9.8) and 31(20) respectively. After conditional logistic regression and multiple hypothesis testing, HLA-DR1 (OR=0.42, CI 0.21-085, P=0.01, PC= 0.09) showed a positive trend towards association with with non RHD controls while HLA-DR11 (OR=3.31, CI 1.57-6.97, P= <0.001, Pc<0.001) was significantly associated with RHD. Other HLA DR alleles were not significantly associated with RHD. Conclusion In this study first of genetic susceptibility to RHD in Uganda, HLADR1 was more common in normal controls while HLADR11 was more common among RHD cases suggesting a disease susceptibility association. Further, high resolution HLA analysis and genome wide studies should be carried out to confirm this pattern as this could potentially provide a mechanism of surveillance of at risk individuals in RHD endemic areas such as Uganda. [