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HLA antigens in an Omani population with dilated cardiomyopathy
International
Journal
of
cardiology International Journal of Cardiology 55 (1996) 29-32
HLA antigens in an Omani population with dilated cardiomyopathy A.K. Agarwal”‘“,
A.G. Whiteb, M. Ali”, W.A. Lehenyb, AS. Daarb
“Department of Medicine, College of Medicine and University Hospital, Sultan Qaboos University, P.O. Box 35 Al Khod, Muscat 123, Sultanate of Oman bDepartment of Surgery, Transplant Immunology Laboratory, College of Medicine and University Hospital, Sultan Qaboos University, P.O. Box 35 Al Khod, Muscat 123, Sultanate of Oman
Received 22 February 1996; accepted 7 March 1996
Abstract We have investigated the frequency of HLA antigens in 50 Omanis with idiopathic dilated cardiomyopathy to establish whether there are ethnic/racial differences in the reported HLA associations with this disease. There were no statistically significant HLA-A, B, C, DR or DQ antigen frequency differences between the patients and 247 healthy Omanis. The reported association of HLA-DR4 with idiopathic dilated cardiomyopathy in the Caucasian population does not apply to the Omanis. This confirms the heterogeneity of this disease and points to ethnic/racial origins as important factors when examining the HLA association. This is particularly pertinent as HLA-DR4 has been strongly linked to autoantibody formation in idiopathic dilated cardiomyopathy in Caucasians. The lack of any HLA antigen association in Omanis would argue against the proposed HLA-linked autoimmune pathology of idiopathic dilated cardiomyopathy. Keywords:
HLA antigens; Idiopathic dilated cardiomyopathy
1. Introduction Idiopathic dilated cardiomyopathy is a disease of unknown aetiology in which genetic and immunological factors have been implicated. The genetic studies have mainly involved the investigation of the association of HLA antigens with the disease, the rationale being the documentation of HLA antigen associations with a broad spectrum of disease including the so-called “autoimmune dis*Corresponding author, Tel.: +968 513333 ext. 4704; Fax: +968 513419.
eases”, of which idiopathic dilated cardiomyopathy may be one [l]. Indeed the inappropriate expression of class II major histocompatibility complex (MHC) molecules on endothelial and endocardial cells supports the “autoimmune” hypothesis [2]. The results of a combined analysis of published data, based largely on Anglo-Scandinavian patients showed an increase in HLA-DR4 and a trend towards the reduction of DR6 [3]. The data in that analysis included results from Pittsburgh, in which no HLA-DR4 association could be demonstrated [4]. A recent study on 98 British patients with idiopathic dilated cardiomyopathy did not show any significant
0167-5273/96/$15.00 0 1996 Elsevier Science Ireland Ltd. All rights reserved SO167-5273(96)02625-3
PII
A.K. Aganval et al. I International
30
increase or decrease in HLA antigens with the disease [5]. The disparity in results and the possibility of racial influences [6] prompted us to investigate the frequency of HLA antigens in Omanis with idiopathic dilated cardiomyopathy.
2. Materials
and methods
Fifty Omani patients with idiopathic dilated cardiomyopathy were included in the study. Informed consent was obtained from each patient and the study conformed with the requirements of the institution’s ethical committee. The diagnosis of idiopathic dilated cardiomyopathy was based on the demonstration of dilated and poorly functioning left or right ventricles or both, as defined by the World Health Organization [7]. The Omani population is comprised of three main ethnic groups originating in Arabia, Africa and Beluchistan. The results were compared with 247 healthy Omanis who were blood donors or potential kidney or bone marrow donors. None of the patients or controls were related to each other. For HLA-A, B, C and DR typing 15-20 ml of blood in ethylenediamine tetra-acetic acid (EDTA) was used. Lymphocytes were separated by density gradient centrifugation and then the B lymphocytes further separated using magnetic beads (class 11 Dynabeads; Dynal, Skoyen, Norway). The supernatam containing T cells was used for HLA-A, B, C typing and the purified B cells for HLA-DR typing. HLA typing was performed using a modified twostage microcytotoxicity technique [8] with ethidium bromidelacridine orange staining and observation with a semi-automated fluorescent microscope. Although class II DNA typing was not perfomed on this group of patients our current experience shows greater than 95% concordance with class II serology. HLA typing sera were obtained from Behringwerke (Marburg, Germany), Pelfreez (Brown Deer, Wisconsin, USA) and Biotest (Dreieich, Germany). The following specificities could be determined: A locus: 1, 2, 3, 9, 10, 11, 19, 23, 24, 25, 26, 28, 29, 30, 31, 32, 33. B locus: 5, 7, 8, 12, 13, 14, 15, 16, 17, 18, 21, 22,
Journal of Cardiology 55 (1996) 29-32
27, 35, 37, 40, 41, 42, 47, 49, 53, 55, 57, Bw4, Bw6. C locus: wl, w2, w3, w4, w5, w6. DR locus: 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 14, 15, 16, DRw52. DQ locus: 1, 2, 3, 7. Statistical analysis was carried out using the chisquare or the Fisher exact test (where appropriate) with the Bonferroni correction obtained by multiplying the P value by the numbers of antigens tested to correct the P value for any chance associations (PC). If the specific antigen association has been reported previously this correction is not necessary [9].
3. Results The results are summarised in Tables l-4. There were no associations of HLA antigens with idiopathic dilated cardiomyopathy that remained significant after correction for the numbers of antigens tested.
Table 1 HLA-A antigen cardiomyopathy HLA-A antigen
Al A2 A3 A9 A10 All Al9 A23 A24 A25 A26 A28 A29 A30 A31 A32 A33
frequencies
IDC n = 50
in Omanis
with
Controls n = 247
Rel. risk
idiopathic
Prob.
dilated
Prob. COIT.
n
%
12
%
[xl
[PI
[P,l
11 22 6 7 4 6 21 2 6 oooo4 5 2 7 1 17 6
22 44 12 14 8 12 42 4 12
36 94 23 33 42 48 93 11 22
15 38 9 13 17 19 38 4 9
1.68 1.28 1.39 1.10 0.46 0.60 1.20 1.06 1.46
-
8 10 4 14 2 34 12
29 27 6 52 9 47 18
12 11 2 21 4 19 7
0.71 0.96 1.91 0.64 0.76 2.20 1.81
0.137 0.264 0.358 0.527 0.076 0.148 0.336 0.621 0.324 0.313 0.540 0.402 0.173 0.476 0.018 0.198
ns, not significant.
ns -
A.K. Agawal Table 2 HLA-B antigen cardiomyopathy HLA-B antigen
B5 B7 B8 B12 B13 B14 B15 B16 Bll B18 B21 1322 B21 B35 B31 B40 B41 B42 B47 B55 B57 BW4 BW6
frequencies
in Omanis
IDC n = 50
Controls n = 247
n
%
n
22 1 4 3 2 0 2 3 11 5 4 1 0 12 0 11 0 1 0 0 1 42 34
44 2 8 6 4 0 4 6 34 10 8 2 0 24 0 22 0 2 0 0 2 84 68
89 9 42 13 8 11 16 10 53 14 24 14 1 13 6 38 1 2 1 9 2 170 172
et al. I International
with
idiopathic
dilated
Rel. risk
Prob.
Prob.
%
InI
WI
lP,l
36 4 17 5 3 4 6 4 21 6 10 6 0 30 2 15 0 1 0 4 1 69 70
1.39 0.76 0.46 1.27 1.45 0.20 0.72 1.66 1.89 1.94 0.88 0.48 1.62 0.71 0.36 1.47 1.62 2.91 1.62 0.24 2.97 2.27 0.91
0.183 0.476 0.076 0.524 0.524 0.127 0.389 0.379 0.046 0.199 0.474 0.247 0.832 0.271 0.327 0.172 0.832 0.426 0.832 0.186 0.426 0.020 0.470
..ns -
COIT.
ns, not significant
4. Discussion Our results support the findings of the Pittsburgh Study [3] in which 91 white patients with dilated cardiomyopathy were studied and the British study
Table 3 HLA-C antigen cardiomyopathy HLA-C antigen
Cwl cw2 cw3 cw4 cw5 Cw6
frequencies
IDC n = 50
in Omanis
Controls n = 247
with
Rel. risk
idiopathic
Prob.
dilated
Prob. corr.
n
%
n
%
1x1
PI
[PC1
1 1 14 16 5 7
2 2 28 32 10 14
8 13 34 83 7 35
3 5 14 34 3 14
0.85 0.52 2.45 0.94 3.87 1.03
0.535 0.283 0.014 0.483 0.035 0.589
ns ns -
ns, not significant
Journal of Cardiology
55 (1996) 29-32
Table 4 HLA-DR and DQ antigen dilated cardiomyopathy HLA-DR antigen
DRl DR2 DR3 DR4 DR5 DR7 DR8 DR9 DRlO DRll DR12
DQl DQ2 DQ3
31
frequencies
in Omanis
with idiopathic
IDC n = 50
Controls n = 209
Rel. risk
Prob.
Prob. corr.
n
%
n
%
[ml
IPI
lP,l
3 39 18 7 8 4 1 0 1 7 0 44 20 13
6 78 36 14 16 8 2 0 2 14 0 88 40 26
19 131 63 32 40 25 2 1 6 28 3 156 79 60
9 63 30 15 19 12 1 0 3 13 1 75 38 29
0.71 2.05 1.31 0.94 0.83 0.70 2.5 1 1.37 0.94 1.09 0.58 2.34 1.10 0.88
0.353 0.027 0.261 0.508 0.388 0.302 0.476 0.807 0.595 0.533 0.524 0.029 0.447 0.424
ns ns -
ns, not significant.
of 98 patients [5]. Neither in the Pittsburgh study, the British study or in the Omani patients could an association with HLA-DR4 be demonstrated. The Pittsburgh study did find a significant increase in HLA-B7 which we did not find (see Table 2). Interestingly however, the Pittsburgh study only found one patient with HLA-B14 (uncorrected P< 0.05) and in Oman not one of the 50 patients had HLA-B14, giving a relative risk of 0.2 although this was not statistically significant (see Table 2). The incidence of HLA-B14 in healthy Omanis is only 4%. It is important to keep the reported HLA-DR4 associations in perspective. In the populations summarised by Carlquist et al. [3] for statistical metaanalysis, the control population frequency of HLADR4 was 27% and idiopathic dilated cardiomyopathy patients 51% (rr = 2.8 and P
Ull.
32
A.K. Agarwal et al. / International
Journal of Cardiology
This evidence for lack of association of HLA-DR4 in other ethnic groups questions the reported HLAlinked autoimmune pathology in this disease. Antibodies to the beta receptor have been strongly linked to the HLA-DR4 phenotype in Caucasian patients 72% of DR4-positive patients having antibodies compared to 22% of the DR4-negative patients [ 121. Thus in Oman, although antibody studies were not carried out there is no evidence for an HLA-DR4linked auto-immune response being involved. A study of north Italian Caucasian patients supports this, where although a significant association with HLA-DR4 and idiopathic dilated cardiomyopathy was reported, no association could be found between HLA-DR4 and organ-specific cardiac antibodies 1131. In summary, idiopathic dilated cardiomyopathy is a heterogeneous disease in which many factors infectious, immunological and genetic - have been implicated. This report demonstrates clearly that racial/ethnic origin is of prime importance.
Acknowledgments We gratefully acknowledge the technical support of Padmavathi Kuchipudi, C. M. Varghese, Hamed Al Riyami and Sulieman Al Hashmi in this study.
References [l] Bender JR. Idiopathic dilated cardiomyopathy. An immunologic, genetic, or infectious disease, or all of the above? Circulation 1991; 83: 704-706. [2] Caforio AL, Stewart JT, Bonifacio E, Burke M, Davies MJ, McKenna WJ, Bottazzo F. Inappropriate major histocompatibility complex expression on cardiac tissue in dilated cardiomyopathy. Relevance for autoimmunity? J Autoimmun 1990; 3: 187-200.
55 (1996) 29-32
[3] Carlquist JF, Menlove RL, Murray MB, O’Connell JB, Anderson JL. HLA class II (DR and DQ) antigen associations in idiopathic dilated cardiomyopathy. Validation study and meta-analysis of published HLA association studies. Circulation 1991; 83: 515-522. [4] Zerbe AR, Kaufman C, Colson Y, Duquesnoy R. Associations of HLA-A, B, DR antigens with primary disease in cardiac allograft recipients. Am J Cardiol 1988; 61: 13591361. [5] Grant SCD, Sheldon S, Dyer PA, Levy RD, Brooks NH. Do specific HLA antigens predispose to ischaemic heart disease or idiopathic dilated cardiomyopathy? Br Heart J 1994; 71: 76-78. [6] Coughlin SS, Woosley RL. Familial dilated cardiomyopathy. Letter to the Editor. N Engl J Med 1992; 326: 1635-1636. [7] Brandenburg RO, Chazov E, Cherian G et al. Report of the WHO/ISFC task force on definition and classification of the cardiomyopathies. Circulation 1981; 64: 437A-438A. [8] Terasaki PI. Microdroplet Cytotoxicity Test. Manual of Tissue-typing Techniques, National Institutes of Health, Bethesda, MD 1976. [9] Svejgaard A, Platz P, Ryder LP. HLA and disease susceptibility: clinical implications. Clin Immun Allergy 1984; 4: 567-580. [lo] Li YY, Zhang JN, Ma WZ. Studies on the genetic susceptibility to dilated cardiomyopathy. Chung Hua Nei Ko Tsa Chih 1993; 32: 25-27. [ 1l] Kishimoto C, Matsumori A, Tomiaka N, Sakurai T, Kawai C. Immunological background of patients with dilated cardiomyopathy and myocarditis: clinical and experimental studies. J Cardiogr (Suppl.) 1986; 9: 19-25. [12] Limas CJ, Limas C. Beta-adrenoceptor antibodies and genetics in dilated cardiomyopathy - an overview and review. Eur Heart J 1991; 12 (Supp1.D): 175-177. [13] Caforio ALP, Martinetti M, Schwarz G et al. Idiopathic dilated cardiomyopathy: lack of association between circulating organ-specific cardiac antibodies and HLA-DR antigens. Tissue Antigens 1992; 39: 236-240.
Journal
of
cardiology International Journal of Cardiology 55 (1996) 29-32
HLA antigens in an Omani population with dilated cardiomyopathy A.K. Agarwal”‘“,
A.G. Whiteb, M. Ali”, W.A. Lehenyb, AS. Daarb
“Department of Medicine, College of Medicine and University Hospital, Sultan Qaboos University, P.O. Box 35 Al Khod, Muscat 123, Sultanate of Oman bDepartment of Surgery, Transplant Immunology Laboratory, College of Medicine and University Hospital, Sultan Qaboos University, P.O. Box 35 Al Khod, Muscat 123, Sultanate of Oman
Received 22 February 1996; accepted 7 March 1996
Abstract We have investigated the frequency of HLA antigens in 50 Omanis with idiopathic dilated cardiomyopathy to establish whether there are ethnic/racial differences in the reported HLA associations with this disease. There were no statistically significant HLA-A, B, C, DR or DQ antigen frequency differences between the patients and 247 healthy Omanis. The reported association of HLA-DR4 with idiopathic dilated cardiomyopathy in the Caucasian population does not apply to the Omanis. This confirms the heterogeneity of this disease and points to ethnic/racial origins as important factors when examining the HLA association. This is particularly pertinent as HLA-DR4 has been strongly linked to autoantibody formation in idiopathic dilated cardiomyopathy in Caucasians. The lack of any HLA antigen association in Omanis would argue against the proposed HLA-linked autoimmune pathology of idiopathic dilated cardiomyopathy. Keywords:
HLA antigens; Idiopathic dilated cardiomyopathy
1. Introduction Idiopathic dilated cardiomyopathy is a disease of unknown aetiology in which genetic and immunological factors have been implicated. The genetic studies have mainly involved the investigation of the association of HLA antigens with the disease, the rationale being the documentation of HLA antigen associations with a broad spectrum of disease including the so-called “autoimmune dis*Corresponding author, Tel.: +968 513333 ext. 4704; Fax: +968 513419.
eases”, of which idiopathic dilated cardiomyopathy may be one [l]. Indeed the inappropriate expression of class II major histocompatibility complex (MHC) molecules on endothelial and endocardial cells supports the “autoimmune” hypothesis [2]. The results of a combined analysis of published data, based largely on Anglo-Scandinavian patients showed an increase in HLA-DR4 and a trend towards the reduction of DR6 [3]. The data in that analysis included results from Pittsburgh, in which no HLA-DR4 association could be demonstrated [4]. A recent study on 98 British patients with idiopathic dilated cardiomyopathy did not show any significant
0167-5273/96/$15.00 0 1996 Elsevier Science Ireland Ltd. All rights reserved SO167-5273(96)02625-3
PII
A.K. Aganval et al. I International
30
increase or decrease in HLA antigens with the disease [5]. The disparity in results and the possibility of racial influences [6] prompted us to investigate the frequency of HLA antigens in Omanis with idiopathic dilated cardiomyopathy.
2. Materials
and methods
Fifty Omani patients with idiopathic dilated cardiomyopathy were included in the study. Informed consent was obtained from each patient and the study conformed with the requirements of the institution’s ethical committee. The diagnosis of idiopathic dilated cardiomyopathy was based on the demonstration of dilated and poorly functioning left or right ventricles or both, as defined by the World Health Organization [7]. The Omani population is comprised of three main ethnic groups originating in Arabia, Africa and Beluchistan. The results were compared with 247 healthy Omanis who were blood donors or potential kidney or bone marrow donors. None of the patients or controls were related to each other. For HLA-A, B, C and DR typing 15-20 ml of blood in ethylenediamine tetra-acetic acid (EDTA) was used. Lymphocytes were separated by density gradient centrifugation and then the B lymphocytes further separated using magnetic beads (class 11 Dynabeads; Dynal, Skoyen, Norway). The supernatam containing T cells was used for HLA-A, B, C typing and the purified B cells for HLA-DR typing. HLA typing was performed using a modified twostage microcytotoxicity technique [8] with ethidium bromidelacridine orange staining and observation with a semi-automated fluorescent microscope. Although class II DNA typing was not perfomed on this group of patients our current experience shows greater than 95% concordance with class II serology. HLA typing sera were obtained from Behringwerke (Marburg, Germany), Pelfreez (Brown Deer, Wisconsin, USA) and Biotest (Dreieich, Germany). The following specificities could be determined: A locus: 1, 2, 3, 9, 10, 11, 19, 23, 24, 25, 26, 28, 29, 30, 31, 32, 33. B locus: 5, 7, 8, 12, 13, 14, 15, 16, 17, 18, 21, 22,
Journal of Cardiology 55 (1996) 29-32
27, 35, 37, 40, 41, 42, 47, 49, 53, 55, 57, Bw4, Bw6. C locus: wl, w2, w3, w4, w5, w6. DR locus: 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 14, 15, 16, DRw52. DQ locus: 1, 2, 3, 7. Statistical analysis was carried out using the chisquare or the Fisher exact test (where appropriate) with the Bonferroni correction obtained by multiplying the P value by the numbers of antigens tested to correct the P value for any chance associations (PC). If the specific antigen association has been reported previously this correction is not necessary [9].
3. Results The results are summarised in Tables l-4. There were no associations of HLA antigens with idiopathic dilated cardiomyopathy that remained significant after correction for the numbers of antigens tested.
Table 1 HLA-A antigen cardiomyopathy HLA-A antigen
Al A2 A3 A9 A10 All Al9 A23 A24 A25 A26 A28 A29 A30 A31 A32 A33
frequencies
IDC n = 50
in Omanis
with
Controls n = 247
Rel. risk
idiopathic
Prob.
dilated
Prob. COIT.
n
%
12
%
[xl
[PI
[P,l
11 22 6 7 4 6 21 2 6 oooo4 5 2 7 1 17 6
22 44 12 14 8 12 42 4 12
36 94 23 33 42 48 93 11 22
15 38 9 13 17 19 38 4 9
1.68 1.28 1.39 1.10 0.46 0.60 1.20 1.06 1.46
-
8 10 4 14 2 34 12
29 27 6 52 9 47 18
12 11 2 21 4 19 7
0.71 0.96 1.91 0.64 0.76 2.20 1.81
0.137 0.264 0.358 0.527 0.076 0.148 0.336 0.621 0.324 0.313 0.540 0.402 0.173 0.476 0.018 0.198
ns, not significant.
ns -
A.K. Agawal Table 2 HLA-B antigen cardiomyopathy HLA-B antigen
B5 B7 B8 B12 B13 B14 B15 B16 Bll B18 B21 1322 B21 B35 B31 B40 B41 B42 B47 B55 B57 BW4 BW6
frequencies
in Omanis
IDC n = 50
Controls n = 247
n
%
n
22 1 4 3 2 0 2 3 11 5 4 1 0 12 0 11 0 1 0 0 1 42 34
44 2 8 6 4 0 4 6 34 10 8 2 0 24 0 22 0 2 0 0 2 84 68
89 9 42 13 8 11 16 10 53 14 24 14 1 13 6 38 1 2 1 9 2 170 172
et al. I International
with
idiopathic
dilated
Rel. risk
Prob.
Prob.
%
InI
WI
lP,l
36 4 17 5 3 4 6 4 21 6 10 6 0 30 2 15 0 1 0 4 1 69 70
1.39 0.76 0.46 1.27 1.45 0.20 0.72 1.66 1.89 1.94 0.88 0.48 1.62 0.71 0.36 1.47 1.62 2.91 1.62 0.24 2.97 2.27 0.91
0.183 0.476 0.076 0.524 0.524 0.127 0.389 0.379 0.046 0.199 0.474 0.247 0.832 0.271 0.327 0.172 0.832 0.426 0.832 0.186 0.426 0.020 0.470
..ns -
COIT.
ns, not significant
4. Discussion Our results support the findings of the Pittsburgh Study [3] in which 91 white patients with dilated cardiomyopathy were studied and the British study
Table 3 HLA-C antigen cardiomyopathy HLA-C antigen
Cwl cw2 cw3 cw4 cw5 Cw6
frequencies
IDC n = 50
in Omanis
Controls n = 247
with
Rel. risk
idiopathic
Prob.
dilated
Prob. corr.
n
%
n
%
1x1
PI
[PC1
1 1 14 16 5 7
2 2 28 32 10 14
8 13 34 83 7 35
3 5 14 34 3 14
0.85 0.52 2.45 0.94 3.87 1.03
0.535 0.283 0.014 0.483 0.035 0.589
ns ns -
ns, not significant
Journal of Cardiology
55 (1996) 29-32
Table 4 HLA-DR and DQ antigen dilated cardiomyopathy HLA-DR antigen
DRl DR2 DR3 DR4 DR5 DR7 DR8 DR9 DRlO DRll DR12
DQl DQ2 DQ3
31
frequencies
in Omanis
with idiopathic
IDC n = 50
Controls n = 209
Rel. risk
Prob.
Prob. corr.
n
%
n
%
[ml
IPI
lP,l
3 39 18 7 8 4 1 0 1 7 0 44 20 13
6 78 36 14 16 8 2 0 2 14 0 88 40 26
19 131 63 32 40 25 2 1 6 28 3 156 79 60
9 63 30 15 19 12 1 0 3 13 1 75 38 29
0.71 2.05 1.31 0.94 0.83 0.70 2.5 1 1.37 0.94 1.09 0.58 2.34 1.10 0.88
0.353 0.027 0.261 0.508 0.388 0.302 0.476 0.807 0.595 0.533 0.524 0.029 0.447 0.424
ns ns -
ns, not significant.
of 98 patients [5]. Neither in the Pittsburgh study, the British study or in the Omani patients could an association with HLA-DR4 be demonstrated. The Pittsburgh study did find a significant increase in HLA-B7 which we did not find (see Table 2). Interestingly however, the Pittsburgh study only found one patient with HLA-B14 (uncorrected P< 0.05) and in Oman not one of the 50 patients had HLA-B14, giving a relative risk of 0.2 although this was not statistically significant (see Table 2). The incidence of HLA-B14 in healthy Omanis is only 4%. It is important to keep the reported HLA-DR4 associations in perspective. In the populations summarised by Carlquist et al. [3] for statistical metaanalysis, the control population frequency of HLADR4 was 27% and idiopathic dilated cardiomyopathy patients 51% (rr = 2.8 and P
Ull.
32
A.K. Agarwal et al. / International
Journal of Cardiology
This evidence for lack of association of HLA-DR4 in other ethnic groups questions the reported HLAlinked autoimmune pathology in this disease. Antibodies to the beta receptor have been strongly linked to the HLA-DR4 phenotype in Caucasian patients 72% of DR4-positive patients having antibodies compared to 22% of the DR4-negative patients [ 121. Thus in Oman, although antibody studies were not carried out there is no evidence for an HLA-DR4linked auto-immune response being involved. A study of north Italian Caucasian patients supports this, where although a significant association with HLA-DR4 and idiopathic dilated cardiomyopathy was reported, no association could be found between HLA-DR4 and organ-specific cardiac antibodies 1131. In summary, idiopathic dilated cardiomyopathy is a heterogeneous disease in which many factors infectious, immunological and genetic - have been implicated. This report demonstrates clearly that racial/ethnic origin is of prime importance.
Acknowledgments We gratefully acknowledge the technical support of Padmavathi Kuchipudi, C. M. Varghese, Hamed Al Riyami and Sulieman Al Hashmi in this study.
References [l] Bender JR. Idiopathic dilated cardiomyopathy. An immunologic, genetic, or infectious disease, or all of the above? Circulation 1991; 83: 704-706. [2] Caforio AL, Stewart JT, Bonifacio E, Burke M, Davies MJ, McKenna WJ, Bottazzo F. Inappropriate major histocompatibility complex expression on cardiac tissue in dilated cardiomyopathy. Relevance for autoimmunity? J Autoimmun 1990; 3: 187-200.
55 (1996) 29-32
[3] Carlquist JF, Menlove RL, Murray MB, O’Connell JB, Anderson JL. HLA class II (DR and DQ) antigen associations in idiopathic dilated cardiomyopathy. Validation study and meta-analysis of published HLA association studies. Circulation 1991; 83: 515-522. [4] Zerbe AR, Kaufman C, Colson Y, Duquesnoy R. Associations of HLA-A, B, DR antigens with primary disease in cardiac allograft recipients. Am J Cardiol 1988; 61: 13591361. [5] Grant SCD, Sheldon S, Dyer PA, Levy RD, Brooks NH. Do specific HLA antigens predispose to ischaemic heart disease or idiopathic dilated cardiomyopathy? Br Heart J 1994; 71: 76-78. [6] Coughlin SS, Woosley RL. Familial dilated cardiomyopathy. Letter to the Editor. N Engl J Med 1992; 326: 1635-1636. [7] Brandenburg RO, Chazov E, Cherian G et al. Report of the WHO/ISFC task force on definition and classification of the cardiomyopathies. Circulation 1981; 64: 437A-438A. [8] Terasaki PI. Microdroplet Cytotoxicity Test. Manual of Tissue-typing Techniques, National Institutes of Health, Bethesda, MD 1976. [9] Svejgaard A, Platz P, Ryder LP. HLA and disease susceptibility: clinical implications. Clin Immun Allergy 1984; 4: 567-580. [lo] Li YY, Zhang JN, Ma WZ. Studies on the genetic susceptibility to dilated cardiomyopathy. Chung Hua Nei Ko Tsa Chih 1993; 32: 25-27. [ 1l] Kishimoto C, Matsumori A, Tomiaka N, Sakurai T, Kawai C. Immunological background of patients with dilated cardiomyopathy and myocarditis: clinical and experimental studies. J Cardiogr (Suppl.) 1986; 9: 19-25. [12] Limas CJ, Limas C. Beta-adrenoceptor antibodies and genetics in dilated cardiomyopathy - an overview and review. Eur Heart J 1991; 12 (Supp1.D): 175-177. [13] Caforio ALP, Martinetti M, Schwarz G et al. Idiopathic dilated cardiomyopathy: lack of association between circulating organ-specific cardiac antibodies and HLA-DR antigens. Tissue Antigens 1992; 39: 236-240.