Tissue Antigens (1977), 10, 361-363 Published by Munksgaard, Copenhagen, Denmark No part may be reproduced by any process without written permissiotl from the author(s)
Histocompatibility Antigens and Myocardial Infarction R.L. Logan,~.R.c.P.,M.R.A.c.P.,' M.F. Oliver, M.D., F.R.c.P.,' Jennifer McTavish, F.I.M.L.S.,? C. Darg, F.I.M.L.S.' and A.G. White, Ph.D. a South-East Scotland
' Department of Cardiology Regional Blood Transfusion Service, Royal Infirmary, Edinburgh, Scotland
HLA typing was carried out in 50 Edinburgh men aged 45 years or under who had experienced a myocardial infarction and in 96 healthy 40-year-old men randomly selected from the same community. No significant differences in antigen frequencies were found, and our results therefore fail to support the hypothesis suggesting an association between HLA-BI and haplotype A1-B8 with ischemic heart disease.
Received for publication 12 April, accepted 27 April 1977
Significant correlations have been demonstrated in Caucasians between the frequencies of histocompatibility antigen HLA-B8 and haplotype A1-B8 and the death rate from ischemic heart disease (IHD) (Mathews 1975). The results of a recent study in England (Scott et al. 1976), which failed to demonstrate any direct association between HLA-B8 and myocardial infarction, were inconclusive, since the age range of the patients was wide (39-80 years) and the prevalence of IHD in the controls was unknown. A study was therefore undertaken in which the frequency of histocompatibility antigens in men who had had a myocardial infarction at a relatively early age was compared with that in a control group of men of similar age from whom the presence of
IHD had been excluded. This study is of particular interest since Scotland, which almost equals Finland's highest mortality rate anywhere from IHD in young men (W.H.O. 19721, also has a high frequency of HLA-B8 and A1-B8 in the population (White et al. 1973, Da Costa et al. 1974).
Materials Patients The names of 66 men who had had a myocardial infarction at the age of 45 years or under were obtained randomly from several sources over a 4-month period. The criteria for myocardial infarction were two of the following from W.H.O. specifications (W.H.O. 1962): a clinical history
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LOGAN ET AL.
of prolonged chest pain, a Q wave ab- failed to achieve the target heart rate of normality in the ECG (Minnesota code 150/min and three from whom samples 1 :1 or 1:2) or raised serum enzymes in for HLA typing were not taken, a control the acute stage. At the time of selection, group of 96 men was obtained. None of there was no other information about these had clinical or electrocardiographic them. They comprised 21 who were evidence of previous myocardial infarction patients in the coronary care unit or gen- or diabetes mellitus. eral medical wards, 30 who had had a myocardial infarction within the previous Methods 2 years and whose names were obtained HLA typing was carried out with lymphofrom the coronary unit register, and 1 5 cytes from defibrinated blood samples who were attending a cardiology out- using the standard N.I.H. tissue typing patients unit following a previous myo- technique. (Ray et al. 1976). A panel of cardial infarction. antisera covering the following specificities In order to make the patient group was used: HLA-Al, A2, A3, A9, A10, comparable to the control group (see A l l , A28, B5, B7, B8, B12, B13, B14, below), 11 patients not resident in or near B17, B27, Bw15, Bw35 and Bw40. Edinburgh at the age of 3 years were exStatistical analysis of the results was cluded. Two diabetics were also excluded carried out using a Yates’ corrected chi because of the known association between square analysis with a correction for the diabetes mellitus and HLA-B8 (Cudworth numbers of antigens tested (Miller 1966). & Woodrow 1975). Blood for phenotyping Haplotype frequencies were calculated by was taken from the remaining 53. To the method of Mattiuz et al. (1970). ensure that there was no bias in selecting R es u2ts patients with significant risk factors it was noted how many had been cigarette The frequencies of the histocompatibility smokers at the time of their infarction or antigens studied, and HLA-B8 in particular, had, at any time, received treatment for did not differ significantly between the hypertension of hyperlipidemia. Any hist- control and patient groups (Table 1). ory of IHD in first degree relatives was Furthermore, in the sub-groups with histrecorded. After excluding three whose ories of cigarette smoking (36), hyperblood samples were unsuitable for lympho- tension and/or hyperlipidemia (10) or with cyte typing, the patient group studied IHD in a first degree relative (26), there comprised 50 men with a mean age of 40.2 were no significant differences in antigen frequencies. years (range 29-45 years). Controls 138 men were randomly selected from 40-year-olds resident in Edinburgh since the age of 3 years. Of these, 107 (77.5%) agreed to take part in an epidemiological study of risk factors for IHD (Olsson et al., 1977). After excluding four with S-Tsegment depression of l m m or more on exercise testing (one with angina), four who
Discussion Our results fail to demonstrate any direct association between HLA-B8 or Al-B8 and survivors of myocardial infarction in Edinburgh in men aged 45 years and under. We cannot exclude the possibility that men who died as a result of their heart attack may have had a higher frequency of HLA-B8 and Al-B8 than those
363
HLA AND MYOCARDIAL INFARCTION
Table 1 Frequency of HLA-A1 and HLA-BI in controls and patients with myocardial infarction HLA-A1
HLA-B8
No. AG. Freq. % Gene Freq. No. Controls (95) 39 Patients ( 5 ) 23 Family History 13 of IHD (26) No Family History of IHD (24) 10
Haplotype
AG. Freq. % Gene Freq. No. %
%
41 46
0.22 0.27
30 19
32 38
0.16 0.21
25 15
26 30
26 30
50
0.29
12
46
0.27
9
35
34
42
0.24
7
29
0.16
6
25
25
No statistically significant differences between Controls v Patients or between Family History v No Family History when tested b y Yates’ corrected xa test with Bonferroni correction (Miller 1966)
who survived. This should be borne in mind when comparing our results with those reported by Mathews (1975) whose data were based on mortality figures. The effect or the known association between HLA-B8 and diabetes mellitus (Cudworth & Woodrow 1975), a risk factor for IHD, was eliminated by excluding men with this disease from both control and patient groups. Since only two of the patient group had hypercholesterolemia requiring treatment, the reported negative association between HLA-B8 and this disorder (Mathews & Tait 1975) is unlikely to have significantly reduced the frequency of the antigen. The frequencies of HLA-B8 and phenotype Al-B8 found in this study were comparable with those reported previously in the Scottish population (White et al. 1973, Da Costa et al. 1974). References Cudworth, A. G. & Woodrow, J. C. (1975) Evidence for HLA-A-linked Genes in “Juvenile” Diabetes Mellitus. Brit. med. J . 3, 133-135. Da Costa, J . A. G., White, A. G . , Parker, A. C. & Grigor, G. B. (1974) Increased incidence of HL-A1 and -8 in patients sharing IgC or complement coating on their red cells. J. Clin. Path. 27, 353-355. Mathews, J. D. (1975) Ischaemic heart disease: possible genetic markers. Lancet ii, 681683.
Mathews, J. D. & Tait, B. D. (1975) HLA-B8 and serumcholesterol. Lancet ii, 1215-1216. Mattiuz, P. L., Ihde, D., Piazza, A., Ceppellini, R. & Bodmer, W. F. (1970) New approaches to the Population Genetic and Segregation Analysis of the HL-A system. Histocompatibility Testing 1970 p. 193-205, Munksgaard, Copenhagen. Miller, R. G. (1966) Simultaneous Statistical Inference p.8, McGraw-Hill, New York. Olsson, A.G., Carlson, L.A., Logan, R.L., Riemersma, R.A., Buchanan, K., LUU, W. & Oliver, M.F. (1977) Differences in lipid and carbohydrate metabolism in relation t o ischaemic heart disease in Edinburgh and Stockholm, Eur. J . Clin. Invest. 7,247. Ray, J. G., Hare, B. D., Pedenen, P. D. &Mullaly, D. I. (1976) N.I.A.I.D. Manual of Tissue Typing Techniques 1976-77 69. D.H.E.W. Publication (NIH), 76-545. Scott, B. B., McGuffin, P., Rajah, S. M., Stoker, J. B. & Losowsky, M. S. (1976) Histocompatibility Antigens and Myocardial Infarction. Tissue Antigens 7, 187-188. White, A. G. Barneston, R. St.C., Da Costa, J. A. G. & McClelland, D. B. L. (1973) The incidence of HL-A antigens in Dermatitis Herpetiformis. Brit. J . Denn. 89, 133-136. W.H.O. (1962) Technical Report 2 3 1 , l S . W.H.O. (1972) World Health Statistics Annual 1,645. Address: M . F. Oliver Department of Cardiology Royal Infirmary Edinburgh Scotland
Histocompatibility Antigens and Myocardial Infarction R.L. Logan,~.R.c.P.,M.R.A.c.P.,' M.F. Oliver, M.D., F.R.c.P.,' Jennifer McTavish, F.I.M.L.S.,? C. Darg, F.I.M.L.S.' and A.G. White, Ph.D. a South-East Scotland
' Department of Cardiology Regional Blood Transfusion Service, Royal Infirmary, Edinburgh, Scotland
HLA typing was carried out in 50 Edinburgh men aged 45 years or under who had experienced a myocardial infarction and in 96 healthy 40-year-old men randomly selected from the same community. No significant differences in antigen frequencies were found, and our results therefore fail to support the hypothesis suggesting an association between HLA-BI and haplotype A1-B8 with ischemic heart disease.
Received for publication 12 April, accepted 27 April 1977
Significant correlations have been demonstrated in Caucasians between the frequencies of histocompatibility antigen HLA-B8 and haplotype A1-B8 and the death rate from ischemic heart disease (IHD) (Mathews 1975). The results of a recent study in England (Scott et al. 1976), which failed to demonstrate any direct association between HLA-B8 and myocardial infarction, were inconclusive, since the age range of the patients was wide (39-80 years) and the prevalence of IHD in the controls was unknown. A study was therefore undertaken in which the frequency of histocompatibility antigens in men who had had a myocardial infarction at a relatively early age was compared with that in a control group of men of similar age from whom the presence of
IHD had been excluded. This study is of particular interest since Scotland, which almost equals Finland's highest mortality rate anywhere from IHD in young men (W.H.O. 19721, also has a high frequency of HLA-B8 and A1-B8 in the population (White et al. 1973, Da Costa et al. 1974).
Materials Patients The names of 66 men who had had a myocardial infarction at the age of 45 years or under were obtained randomly from several sources over a 4-month period. The criteria for myocardial infarction were two of the following from W.H.O. specifications (W.H.O. 1962): a clinical history
362
LOGAN ET AL.
of prolonged chest pain, a Q wave ab- failed to achieve the target heart rate of normality in the ECG (Minnesota code 150/min and three from whom samples 1 :1 or 1:2) or raised serum enzymes in for HLA typing were not taken, a control the acute stage. At the time of selection, group of 96 men was obtained. None of there was no other information about these had clinical or electrocardiographic them. They comprised 21 who were evidence of previous myocardial infarction patients in the coronary care unit or gen- or diabetes mellitus. eral medical wards, 30 who had had a myocardial infarction within the previous Methods 2 years and whose names were obtained HLA typing was carried out with lymphofrom the coronary unit register, and 1 5 cytes from defibrinated blood samples who were attending a cardiology out- using the standard N.I.H. tissue typing patients unit following a previous myo- technique. (Ray et al. 1976). A panel of cardial infarction. antisera covering the following specificities In order to make the patient group was used: HLA-Al, A2, A3, A9, A10, comparable to the control group (see A l l , A28, B5, B7, B8, B12, B13, B14, below), 11 patients not resident in or near B17, B27, Bw15, Bw35 and Bw40. Edinburgh at the age of 3 years were exStatistical analysis of the results was cluded. Two diabetics were also excluded carried out using a Yates’ corrected chi because of the known association between square analysis with a correction for the diabetes mellitus and HLA-B8 (Cudworth numbers of antigens tested (Miller 1966). & Woodrow 1975). Blood for phenotyping Haplotype frequencies were calculated by was taken from the remaining 53. To the method of Mattiuz et al. (1970). ensure that there was no bias in selecting R es u2ts patients with significant risk factors it was noted how many had been cigarette The frequencies of the histocompatibility smokers at the time of their infarction or antigens studied, and HLA-B8 in particular, had, at any time, received treatment for did not differ significantly between the hypertension of hyperlipidemia. Any hist- control and patient groups (Table 1). ory of IHD in first degree relatives was Furthermore, in the sub-groups with histrecorded. After excluding three whose ories of cigarette smoking (36), hyperblood samples were unsuitable for lympho- tension and/or hyperlipidemia (10) or with cyte typing, the patient group studied IHD in a first degree relative (26), there comprised 50 men with a mean age of 40.2 were no significant differences in antigen frequencies. years (range 29-45 years). Controls 138 men were randomly selected from 40-year-olds resident in Edinburgh since the age of 3 years. Of these, 107 (77.5%) agreed to take part in an epidemiological study of risk factors for IHD (Olsson et al., 1977). After excluding four with S-Tsegment depression of l m m or more on exercise testing (one with angina), four who
Discussion Our results fail to demonstrate any direct association between HLA-B8 or Al-B8 and survivors of myocardial infarction in Edinburgh in men aged 45 years and under. We cannot exclude the possibility that men who died as a result of their heart attack may have had a higher frequency of HLA-B8 and Al-B8 than those
363
HLA AND MYOCARDIAL INFARCTION
Table 1 Frequency of HLA-A1 and HLA-BI in controls and patients with myocardial infarction HLA-A1
HLA-B8
No. AG. Freq. % Gene Freq. No. Controls (95) 39 Patients ( 5 ) 23 Family History 13 of IHD (26) No Family History of IHD (24) 10
Haplotype
AG. Freq. % Gene Freq. No. %
%
41 46
0.22 0.27
30 19
32 38
0.16 0.21
25 15
26 30
26 30
50
0.29
12
46
0.27
9
35
34
42
0.24
7
29
0.16
6
25
25
No statistically significant differences between Controls v Patients or between Family History v No Family History when tested b y Yates’ corrected xa test with Bonferroni correction (Miller 1966)
who survived. This should be borne in mind when comparing our results with those reported by Mathews (1975) whose data were based on mortality figures. The effect or the known association between HLA-B8 and diabetes mellitus (Cudworth & Woodrow 1975), a risk factor for IHD, was eliminated by excluding men with this disease from both control and patient groups. Since only two of the patient group had hypercholesterolemia requiring treatment, the reported negative association between HLA-B8 and this disorder (Mathews & Tait 1975) is unlikely to have significantly reduced the frequency of the antigen. The frequencies of HLA-B8 and phenotype Al-B8 found in this study were comparable with those reported previously in the Scottish population (White et al. 1973, Da Costa et al. 1974). References Cudworth, A. G. & Woodrow, J. C. (1975) Evidence for HLA-A-linked Genes in “Juvenile” Diabetes Mellitus. Brit. med. J . 3, 133-135. Da Costa, J . A. G., White, A. G . , Parker, A. C. & Grigor, G. B. (1974) Increased incidence of HL-A1 and -8 in patients sharing IgC or complement coating on their red cells. J. Clin. Path. 27, 353-355. Mathews, J. D. (1975) Ischaemic heart disease: possible genetic markers. Lancet ii, 681683.
Mathews, J. D. & Tait, B. D. (1975) HLA-B8 and serumcholesterol. Lancet ii, 1215-1216. Mattiuz, P. L., Ihde, D., Piazza, A., Ceppellini, R. & Bodmer, W. F. (1970) New approaches to the Population Genetic and Segregation Analysis of the HL-A system. Histocompatibility Testing 1970 p. 193-205, Munksgaard, Copenhagen. Miller, R. G. (1966) Simultaneous Statistical Inference p.8, McGraw-Hill, New York. Olsson, A.G., Carlson, L.A., Logan, R.L., Riemersma, R.A., Buchanan, K., LUU, W. & Oliver, M.F. (1977) Differences in lipid and carbohydrate metabolism in relation t o ischaemic heart disease in Edinburgh and Stockholm, Eur. J . Clin. Invest. 7,247. Ray, J. G., Hare, B. D., Pedenen, P. D. &Mullaly, D. I. (1976) N.I.A.I.D. Manual of Tissue Typing Techniques 1976-77 69. D.H.E.W. Publication (NIH), 76-545. Scott, B. B., McGuffin, P., Rajah, S. M., Stoker, J. B. & Losowsky, M. S. (1976) Histocompatibility Antigens and Myocardial Infarction. Tissue Antigens 7, 187-188. White, A. G. Barneston, R. St.C., Da Costa, J. A. G. & McClelland, D. B. L. (1973) The incidence of HL-A antigens in Dermatitis Herpetiformis. Brit. J . Denn. 89, 133-136. W.H.O. (1962) Technical Report 2 3 1 , l S . W.H.O. (1972) World Health Statistics Annual 1,645. Address: M . F. Oliver Department of Cardiology Royal Infirmary Edinburgh Scotland
