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Asian Cardiovasc Thorac Ann 2004;12:107-110
© 2004 Asia Publishing EXchange Ltd

ORIGINAL CONTRIBUTION

Human Leukocyte Antigens in Hypertrophic Cardiomyopathy Patients in South India

Umapathy Shankarkumar, PhD, Ramasamy Pitchappan, PhD, Srinivasan Pethaperumal, MD

Department of Immunology, School of Biological Sciences, Madurai Kamaraj University, Madurai, India

For reprint information contact: Umapathy Shankarkumar, PhD Tel: 91 22 413 8518 Fax: 91 22 413 8521 Email: shankarkumar16{at}hotmail.com Institute of Immunohaematology, 13th Floor, KEM Hospital, Parel, Mumbai 400012, India.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Hypertrophic cardiomyopathy is characterized by massive ventricular hypertrophy, reduced diastolic function, and excessive ventricular contraction. The human leukocyte antigens HLA-A, HLA-B, and HLA-DR were studied in 14 hypertrophic cardiomyopathy patients with left ventricular obstruction from South India. They were compared with 81 normal age- and sex-matched individuals from the same ethnic background. The human leucocyte antigens were identified using the standard serological assay with a longer incubation for DR antigens. The odds ratio, frequency, chi-squared value, p-value, etiological fraction, preventive fraction, and haplotype frequency estimates were calculated. The HLA-B51 and HLA-DR2 levels were significantly increased in hypertrophic cardiomyopathy patients compared to controls, whereas HLA-A19, HLA-B7, and HLA-DR4 were decreased when compared to the controls. It was noticed that haplotype B51-DR2-DQ3 was significantly associated with hypertrophic cardiomyopathy patients from South India. Hypertrophic cardiomyopathy may be associated with genes in the human leukocyte antigen region, and immunogenetic factors linked to human leukocyte antigens appear to play a major role in the pathogenesis.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
A comparative study conducted in Port of Spain, Trinidad, among 1343 males and 1149 females aged 35–69 years, comprising African, Indian, European, and Chinese ethnic groups, showed that mortality was significantly higher in Indians and Africans with cardiovascular disease.1 These groups, sharing a common environment, suggest the possibility of a genetic component of the ethnic differences in cardiovascular deaths. Hypertrophic cardiomyopathy is a hypertrophied left ventricle (asymmetric thickening of the wall, usually predominantly involving the ventricular septum) without abnormal enlargement of the ventricular cavities. Hypertrophic cardiomyopathy is relatively rare, occurring in no more than 2% of the USA population. In India, the incidence is higher; individuals of Asian Indian origin have a 3- to 4-fold increased risk of heart disease, which appears to be inherited, and affects men and women of all ages.2 People with hypertrophic cardiomyopathy often have no signs of the disease. Hypertrophic cardiomyopathy varies widely in its symptoms and in many cases, the disease results in congestive heart failure.2 The heart muscles are highly adaptive and can enlarge when they are being strained by heart valves that do not function properly, or by high blood pressure. These enlarged muscles make the heart walls thicker and able to beat more strongly, however, such thickening can also obstruct the blood flow. The ability of the heart muscle to regulate its thickness is controlled by specific genes. Mutations in these genes cause hypertrophy even when the heart is not under strain. This inappropriate thickening of the heart muscle leads to hypertrophic cardiomyopathy. Approximately 60%-70% of people who develop hypertrophic cardiomyopathy have inherited a gene that predisposes them to the disease. These mutations are inherited in an autosomal dominant fashion. Human leukocyte antigen (HLA) associations have been implicated in hypertrophic cardiomyopathy patients studied from all over the world.3–9 The fact that Indians are genetically susceptible to heart disease prompted this study some years ago, but the data were not reported. Recently, when searching the literature, it was noted that there were no data on hypertrophic cardiomyopathy and HLA from India, which instigated the analysis of our results so many years later.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Over the period of one year (1989–1990), 14 hypertrophic cardiomyopathy patients with clinical symptoms, attending the Grace Kennet Hospital, Madurai, were included in the study. The diagnosis was confirmed by echocardiograms, doppler studies, treadmill tests, and cardiac catheterization when necessary, showing left ventricular obstruction (septal measurements > 1.5 mm) The patients’ ages ranged from 50 to 70 years. They were usually treated with beta blockers and/or calcium antagonists. As a control group, 81 age- and sex-matched normal healthy staff and students of Madurai Kamaraj University, from the same ethnic background, were also tested. Informed consent was obtained from each individual. The clinical details and demographics of the control and patient groups were recorded in a questionnaire.

For HLA typing, 10–15 mL of venous blood (in heparin 50 IU•mL–1) was collected in a sterile tube from each individual. The lymphocytes were isolated by density gradient centrifugation on Histopaque.10 The HLA-A, HLA-B, HLA-C, and HLA-DR locus antigens were identified by the two-stage microlymphocytotoxicity assay, using T-cells for class I typing and B cells isolated by a miniature nylon wool column for class II, with a longer incubation period.11,12 A total of 190 indigenous antisera were used for defining 17 specificities for HLA-A locus, 29 for HLA-B locus, 8 for HLA-C locus, and 10 for HLA-DR locus antigens.13 The typing tray included a minimum of 3 antisera for each supertype specificity.

The phenotype frequencies, odds ratio, probability value, value of chi-squared with the Yates correction, etiological and preventive fractions were estimated using our database and computer programs.14 Since each individual was tested for several HLA alleles and the same data were used for comparing the frequency, it is possible that one of the alleles might deviate significantly by chance. To overcome this error, the p-value was corrected by the Bonferroni inequality method, multiplying it by the number of alleles compared.15


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The HLA antigen frequency observed among the hypertrophic cardiomyopathy patients is compared with that found in the controls in Table 1Go. A high odds ratio was observed for HLA-A2, A11, B13, B51, DR2, DR4 and DR6, while a reduced odds ratio was obtained for HLA-A1, A28, B7, DR7, DR8, and DR9. A significant odds ratio was found for HLA-B51. Further, it was noted that haplotype A2-B51-DR2 had a significant association among the hypertrophic cardiomyopathy patients.


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  		Table 1. HLA Association in Hypertrophic Cardiomyopathy
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The genetic susceptibility of a population to a particular disease can be known through the study of HLA genetics. As the genes come from parental segregation, genetic screening can predict the risk of development of the disease, and the disease can be detected before onset or at a very early stage. It is well known that the Indian population is genetically susceptible to mental disorders, autoimmune diseases, diabetics, infectious diseases, and heart diseases. Earlier studies have shown that Indians have a high incidence of heart disease.1 Researchers have identified several genes that can cause hypertrophic cardiomyopathy. All the genes identified so far are part of the mechanism that allows the heart muscle to contract, beta-myosin heavy chain, alpha-tropomyosin, cardiac troponin-T, myosin-binding protein C, and an unidentified gene on chromosome 7.16–19 Commercial genetic testing is not yet available for a mutation that predisposes a person to hypertrophic cardiomyopathy.

The HLA studies in hypertrophic cardiomyopathy patients from around the world have shown varied inconsistent as well as consistent associations. Recently, molecular typing in hepatitis C virus-positive hypertrophic cardiomyopathy patients for HLA class II have shown that the haplotype DRB1*0901-DQB1*0303 may be involved the development of hypertrophic cardiomyopathy mediated by the hepatitis C virus.9 This study showed a significant HLA association with HLA-B51 and the haplotype A2-B51-DR2, attributing a significant association for developing hypertrophic cardiomyopathy with left ventricle obstruction. Our findings suggest that HLA-B51 and the related haplotype may play a role in the pathogenesis of hypertrophic cardiomyopathy in Indian patients. However, we feel that this study should be repeated with the application of molecular techniques in a larger patient population from India. The findings in this study are compared on Table 2Go with the HLA allele associations reported from hypertrophic cardiomyopathy patients around the world. It can be seen that different HLA alleles were associated with different populations of hypertrophic cardiomyopathy patients.


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  		Table 2. HLA Associations in Hypertrophic Cardiomyopathy Patients in Various Populations
 


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Beckles GL, Miller GJ, Kirkwood BR, Alexis SD, Carson DC, Byam NT. High total and cardiovascular disease mortality in adults of Indian descent in Trinidad, unexplained by major coronary risk factors. Lancet 1986;1(8493):1298–301.[Medline]

  2. Coonar AS, McKenna WJ. Hypertrophic cardiomyopathy. In: Poole-Wilson PA, Colucci WS, Massie BM, Chatterjee K, Coats AJS, editors. Heart failure. Scientific principles and clinical practice. New York: Churchill Livingstone, 1997:379–99.

  3. Mourant AJ, Kafetz KM, Brigden WW, Awad J, D’Amaro J, Yeatman NW, et al. HLA antigen association in hypertrophic cardiomyopathy. Tissue Antigens 1982;20:389–93.[Medline]

  4. Gardin JM, Gottdiener JS, Radvany R, Maron BJ, Lesch M. HLA linkage vs association in hypertrophic cardiomyopathy. Evidence for the absence of an association in a heterogeneous Caucasian population. Chest 1982;81:466–72.[Abstract/Free Full Text]

  5. Fiorito S, Autore C, Fragola PV, Purpura M, Cannata D, Sangiorgi M. HLA-DR3 antigen linkage in patients with hypertrophic obstructive cardiomyopathy. Am Heart J 1986;111:9–4.

  6. Majsky A, Gregor P, Prazak J. HLA-A, B-antigens and hypertrophic cardiomyopathy [German]. Z Gesamte Inn Med 1989;44:361–2.[Medline]

  7. Gregor P, Ivaskova E, Sajdlova H, Kupkova L, Widimsky P, Cervenka V. Immunogenetic study in hypertrophic cardiomyopathy [Czech]. Vnitr Lek 1992;38:466–72.[Medline]

  8. Wesslen L, Waldenstrom A, Lindblom B, Hoyer S, Friman G, Fohlman J. Genotypic and serotypic profile in dilated cardiomyopathy. Scand J Infect Dis Suppl 1993;88:87–91.[Medline]

  9. Naruse TK, Inoko H. HLA and hepatitis C virus positive cardiomyopathy [Japanese]. Nippon Rinsho 2000;58:212–7.

  10. Boyum A. Separation of leucocytes from blood and bone marrow. Introduction. Scand J Clin Lab Invest Suppl 1968;21:97–99.

  11. Terasaki PI, McClelland JD. Microdroplet assay of human serum cytotoxins. Nature 1964;204:998–1000.[Medline]

  12. Manickasundari M, Selvaraj P, Pitchappan RM. Studies on T-cells of the lizard, Calotes versicolor: adherent and non-adherent population of the spleen. Dev Comp Immunol 1984;8:367–74.[Medline]

  13. Pitchappan RM, Amutha S, Mahendran V, Brahmajothi V, Shankarkumar U, Balakrishnan K, et al. Collection of anti HLA antibodies in South India. J Biosci 1993;18:373–80.

  14. Shankarkumar U, Devraj JP, Ghosh K, Mohanty D. Seronegative spondarthritis and human leucocyte antigen association. Br J Biomed Sci 2002;59:38–41.[Medline]

  15. Dunn OJ. Multiple comparison among means. Am J Stat Assoc 1961;56:52–6.

  16. Carrier L, Hengstenberg C, Beckmann JS, Guicheney P, Dufour C, Bercovici J, et al. Mapping of a novel gene for familial hypertrophic cardiomyopathy to chromosome 11. Nat Genet 1993;4:311–3.[Medline]

  17. MacRae CA, Ghaisas N, Kass S, Donnelly S, Basson CT, Watkins HC, et al. Familial hypertrophic cardiomyopathy with Wolff-Parkinson-White syndrome maps to a locus on chromosome 7q3. J Clinical Invest 1995;96:1216–20.[Medline]

  18. Thierfelder L, Watkins H, MacRae C, Lamas R, McKenna W, Vosberg HP, et al. Alpha-tropomyosin and cardiac troponin T mutation cause familial hypertrophic cardiomyopathy: disease of the sarcomere. Cell 1994;77:701–12.[Medline]

  19. Watkins H, McKenna WJ, Thierfelder L, Suk HJ, Anan R, O’Donoghue A, et al. Mutations in gene for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy. New Engl J Med 1995;332:1058–64.[Abstract/Free Full Text]





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