PATHOPHYSIOLOGY AND NATURAL HISTORY RHEUMATIC HEART DISEASE HLA-A, B, DR, and DQ antigens in black patients with severe chronic rheumatic heart disease

To determine whether genetic factors could be involved in the pathogenesis of rheumatic heart disease, we performed HLA-A and HLA-B typing in 120 black patients with severe chronic rheumatic heart disease requiring cardiac surgery, and HLA-DR and HLA-DQ typing in 103 and 97 of these patients, respectively. The HLA typing was done by a standard microlymphocytotoxicity method. Patients were 12 to 60 years old (mean 27.6 ± 14.5). No differences in HLA-A, HLA-B, and HLA-DQ frequencies between patients and controls were noted. HLA-DR 1 antigen was present in 12.6% of patients compared with 2.7% of normal control subjects (corrected p<.045; relative risk = 5.2) and the HLA-DRw6 antigen was present in 31.1% of patients compared with 15% of control subjects (corrected p<.045; relative risk = 2.6). These findings suggest that genetically determined immune-response factors may play a role in the pathogenesis of severe chronic rheumatic heart disease. Circulation 76, No. 2, 259-261, 1987. THE HLA antigens, which are encoded by closely arranged genes on the short arm of the sixth chromosome, influence the predisposition to several diseases. Some diseases with initially weak associations with HLA-A and HLA-B antigens have been found to have stronger associations with HLA-DR antigens.2 Since a genetic predisposition to the development of rheumatic fever has been documented,3'4 and since there is little information on the relationship between antigens at the DR-locus of the HLA system and chronic rheumatic heart disease, we performed HLA typing in a group of black patients with this disease to determine whether genetic factors could be involved in the pathogenesis of rheumatic heart disease. Patients and methods HLA-A and HLA-B typing was carried out in 120 black patients with severe chronic rheumatic heart disease, as defined by the World Health Organization,5 who required cardiac surgery at the Cardiothoracic Surgical Unit, Wentworth Hospital, Durban, and HLA-DR and HLA-DQ typing was performed in 103 and 97 of these patients, respectively. The distribution of From the Departnments of Clinical and Experimental Pharmacology and Medicine, Faculty of Medicine, University of Natal and Natal Institute of Immunology, Durban, South Africa. Supported by grants from the Faculty of Medicine Research Fund and South African Medical Research Council. Address for correspondence: Dr. B. Maharaj, Department of Clinical and Experimental Pharmacology, Faculty of Medicine, P.O. Box 17039, Congella 4013, Durban, South Africa. Received Nov. 18, 1986; revision accepted April 16, 1987. Vol. 76, No. 2, August 1987 valvular lesions was as follows: isolated mitral stenosis, 36 patients; mitral stenosis plus aortic incompetence, one patient; mitral stenosis and aortic incompetence with aortic stenosis (mixed aortic valve disease), one patient; mitral incompetence alone, five patients; mitral plus aortic incompetence, 18 patients; mitral stenosis with mitral incompetence (mixed mitral valve disease), 32 patients; mixed mitral valve disease plus aortic incompetence, 17 patients; mixed mitral valve disease plus mixed aortic valve disease, three patients; mixed aortic valve disease, three patients; isolated aortic incompetence, four patients. In each case the rheumatic etiology of the valve lesions was confirmed by inspection of the valve at surgery or on histologic examination of the valve. Many patients were having their second or third operation. There were 80 female and 40 male patients between 12 and 60 years old. Their mean age was 27.6 ± 14.5 years; 60% of the patients fell within the 12 to 25 year age group. The control group consisted of 1416 normal adults for the HLA-A and HLA-B typing, 220 for the HLA-DR and 64 for the HLA-DQ typing. Although over 2000 individuals have been tested for the HLA-DQ locus in our laboratory the majority were Caucasoid or patients with selected diseases.6 As a consequence, only 64 normal healthy black individuals had undergone DQ typing. The HLA-A and HLA-B antigens were identified with a twostage lymphocytotoxicity test.7 These antigens were defined with 180 antisera, which consisted of local serum samples that had been requested for use in Intemational Histocompatibility Workshops, local samples that had been verified by use in parallel with the International Workshop samples, and samples that had been exchanged with other laboratories worldwide.8-12 Similarly, 120 serum samples were used to define the HLA-DR and HLA-DQ antigens in B cell-enriched lymphocyte suspensions prepared with the use of straws packed with nylon wool. 13 The differences in frequency of the various antigens between patients and controls were tested for significance by means of the chi-square test (without Yates' correction). The resulting probabilities were multiplied by the number of HLA specific259 by gest on Sptem er 6, 2017 http://ciajournals.org/ D ow nladed from