Pediatr Cardioi 13:204-207, 1992

Pediatric Cardiology 9 Springer-Verlag New York Inc. 1992

H L A a n d R h e u m a t i c F e v e r in T u r k i s h C h i l d r e n Hashem E. Khosroshahi, 1 0 z Kahramanyol,~ and Levent Do~anci 2 ~Division of Pediatric Cardiology, Social Security Children's Hospital, Di~kapi, Ankara, Turkey: and -~Infectious Diseases Clinic and Immunology Department, Gi~lhane Military Medical Academy, Ankara. Turkey

SUMMARY. We report the results of research on human leukocyte ailo-antigen (HLA) and rheumatic fever (RF), the first published study to be carried out among Turkish children with RF. Ninety-three Turkish children, aged between 6 and 16 years (mean: 8 - 2.6), with RF participated in the study. Of the total, 26 patients had their first attack and 39 had acute rheumatic activity at the time of registration. The results demonstrate (1) negative but not significant association between HLA-A2 and RF; (2) a positive association between HLA-DR4 and RF (p < 0.001); (3) a significant association between HLA-DR4 and carditis, but not with isolated arthritis. These results corroborate the concept of race-specific genetically determined familial susceptibility to the development of rheumatic heart disease. KEY WORDS: HLA - - Rheumatic carditis - - Rheumatic fever

The association between several autoimmune diseases and HLA-DR, an immune-response gene product, has been well documented in the literature. There is a general acceptance that rheumatic fever (RF) is related to familial susceptibility (i.e., genetically influenced). Its pathogenesis is thought to be influenced through human leukocyte aiM-antigen (HLA) produced by closely arranged genes on the sixth chromosome. This may explain the high familial incidence of RF and has much to do with the immune response evoked by group A streptococci. However, because of a contradictory relationship between RF and class I HLA antigens (A, B, and C) and also limited available data concerning the RF and class II antigens, we performed HLA typing to determine the role of genetic factor(s), predisposing to the development of RF, among Turkish children.

Patients and Methods We investigated 93 Turkish children, aged between 6 and 16 years (mean: 8 -+ 2.6) (male/female ratio: 44/49), who had RF. The modified Jones' criteria [1] were used in the diagnosis, 26 Address offprint requests to." Assoc. Prof. Dr. Hashem E. Khosroshahi, 3050 Ellesmere Road, No. 606, Scarborough, Ontario, M1E 5E6, Canada.

patients had their first attack and 39 had acute rheumatic activity at the time of enrollment in the study. Seventy children had carditis and 18 isolated arthritis. The control group consisted of unrelated subjects who were selected randomly from healthy donors of the Bone Marrow Transplantation Center of the G01hane Military Medical Academy, Ankara. There were 218 subjects for HLA A, B, and C typing and 80 for HLA-DR. The standard microtoxicity technique of Terasaki and modified N IH methods were used for determination of class 1 and I1 antigens [3, 29]. Student's t lest, chi square, and Fisher's exact probability test [9] were used for comparison and to calculate significance. The definition of statistical significancies was modified [14]. The relative risk calculation and correction was undertaken

Table 1. HLA-DR antigens in Turkish children with RF HLA

DR1 DR2 DR3 DR4 DR5 DR7 DRw52 DRw53

Patients (n - 93)

Controls (n = 80)

n

%

n

%

20 12 20 35 9 30 31 4

21.5 12.9 21.5 37.6 9.7 32.2 33.3 4.3

20 12 19 6 12 15 17 9

25 16.2 23.7 7.5 15 18.7 21.2 11.2

RR

EF

0.82 0.84 0.88 7.4 0.6 2.06 1.85 0.35

1.38 2.08 1.78 0.97 1.26 0.94 0.93 0.08

(-) (-) (-) (+) (-) (+) (+) (-)

RR, Relative risk, EF, etiologic fraction; ( - ) , negative association; (+), positive association.

K h o s r o s h a h i et al.: H L A and R h e u m a t i c F e v e r

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Table 2. Major manifestations and significance of the incidence of H L A - D R antigens in Turkish children with RF Clinical manifestation All RF n

X'p RR Arthritis n X2 p RR Chorea" n X2 p RR Carditis n X~p RR Chronic isolated mitral insufficiency n X-~ P RR

DR1

DR2

DR3

DR4

DR5

DR7

DRw52

DRw53

20 0.29 NS 0.82

12 0.38 NS 0.84

20 0.01 NS 0.88

35 19.96 0.001 7.4

9 3.65 NS 0.6

30 4.07 NS 2.06

31 3.13 NS 1.85

4 2.07 NS 0.35

5 0.03 NS 1.15

4 0,07 NS 1,47

5 0.08 NS 1.23

4 2.05 NS 3.52

3 0.01 NS 0.74

8 4.06 NS (1.8(1

5 0.08 NS 3.03

--

I 0,27 NS 0.38

4 2.54 NS 4.12

1 a NS 0.40

4 a NS 9.87

2 a NS 1.06

3 a NS 2.17

2 a NS 1.06

--

15 0.27 NS 0.82

8 0.38 NS 0.93

15 0.01 NS 1.66

31 25.24 0.0001 9.80

6 3.56 NS 0.35

22 3.23 NS 1.99

26 4.61 NS 2.29

4 0.83 NS 0.48

10 0.24 NS 1.25

4 0.11 NS 0.68

8 0.05 NS 1,66

17 24.18 0.0001 12.33

3 1.76 NS 0.36

8 0. I 1 NS 1.33

13 3.55 NS 2.29

3 0.03 NS 0.76

X-', chi square; p, probability level; RR, relative risk; NS, not significant; a, Fisher's exact probability test was used for comparisons. " Five of nine cases as isolated chorea.

as described elsewhere [18] and etiologic fraction (EF) calculated

Discussion

as

EF =

P (RR - I) P (RR- I)+ 1

where P is the frequency a m o n g the normal population and RR is the relative risk.

Results

The results are presented in Tables 1 and 2. Among class I antigens the frequency of HLA-A2 was decreased, while the frequency of HLA-B5 and of class II HLA-DR7 was increased. However, none was statistically significant. The correlation between RF and HLA-DR4 (p < 0.001) was significant. There was no statistically significant association between arthritis, either with class I or class II antigens. The patients with carditis showed a modest (p < 0.05) positive association with HLADRw52. The frequency of HLA-DR4 among 34 patients with isolated chronic mitral regurgitation was particularly high at 50% (p < 0.0001).

Many attempts have been made to explain the pathogenesis of RF genetically by searching for an association with H L A antigens. Particular attention has been paid to HLA-DR antigens, which are related to the immune-response genes encoded on the short arm of the sixth chromosome. The corresponding results of our study are summarized in Table 3. Despite the lacking relationship between class I H L A antigens and RF, there is a general acceptance of the positive relationship between class II H L A antigens and increased genetically linked susceptibility for RF and rheumatic heart disease. It is known that the preceding infection with group A streptococci is required as an inciting factor to trigger the rheumatic process. Previous studies [12, 26] have shown that the immune response to group A streptococcal carbohydrate is genetically controlled. Also, Ayoub et al. [5] have described a significant association between persistence of antibody to the group A streptococcal carbohydrate and HLA-DR2 in a black population and HLA-DR4 in

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Pediatric Cardiology Vol. 13, No. 4, 1992

Table 3. HLA association with RF Study population

Caucasians Maoris Europeans Indians Finnish Mexican-American Japanese Americans Caucasians American blacks Indians Martinique S. African blacks Saudi Arabs North Indians

HLA association Increased

Decreased

-A3,B8 B l7 -B35 BI8 B5 AI 1,B7 DR4 B5,DR4,DR9 A23,DR2 DR3 B35 DRI,DRw6 DR4 DR3,DQw2

A3 A10 A28 B5 ---DR6 -A2 -B 14,Bw42 --DR2

Number of cases

Year

Reference

RF,RHD RF,RHD RF,RHD RF,RHD RF RHD RF RF,RHD RHD RF RF RHD RF RHD RF,RHD RHD

1973 1975 :[975 1977 1977 1977 1978 1983 1986 1986 1986 1986 1986 1987 1987 1989

13 6 6 25 17 17 21 27 4 18 18 15 20 19 24 28

(76) (50) (50) (34) (109) (86) (49) (185) (33) (24) (48) (56) (88) (103) (40) (54)

RF Rheumatic fever; RHD, rheumatic heart disease.

Caucasians with RF. Dudding and Ayoub [11] have reported that the persistence of high antibody titers against group A streptococcal carbohydrate is limited to patients with rheumatic valvar disease and is not seen in patients with RF but no cardiac involvement. It is generally agreed that the immune-response gene products are in fact the HLA class II molecules themselves [23], and Amoils [2] has reported HLA-DR-positive fibroblasts in cardiac tissue and in the valves with histopathologically acute activity, in patients with RF. Disciasico [10] stated that, in the absence of a recurrence, new valvar lesions do not appear, and the severity of rheumatic heart disease at follow-up is generally proportional to the severity of the acute carditis. The present study revealed that the increased frequency of HLA-DR4 positivity in Turkish children is associated with an increased risk of developing RF and provides evidence of a positive association between HLA-DR4 and rheumatic carditis, but not with arthritis. According to Ayoub [5], the absence of a significant association between HLA-DR antigens and arthritis emphasizes the low specificity of "arthritis" as a major manifestation of RF. However, our study has failed to explain the genetically predisposing factor(s) among patients with a lack of such significant antigenic basis. Zabriskie [30] has reported the presence of B-cell surface antigen 83S19.23 in approximately 20% of the worldwide normal population. This would make individuals in this group vulnerable and hence at risk

of contracting the disease. Zabriskie [31] also reported the presence of non-HLA B-cell antigen D8/ 17 in all RF patients of North American origin. This latter antigen has been found in about 63% of RF patients fi'om North India [28]. There are strong reasons for a possible modification of Jones' criteria, using the combination of HLA-DR association and persistence of high antibody titers to group A streptococcal carbohydrate [5] or the non-HLA antigen D8/17 [16] in the diagnosis of patients suspected of having RF. A positive association between HLA-DR4 and some antoimmune diseases other than RF has been observed [7, 8, 22]. Further studies concerning the structural polymorphism of class II molecules should be considered to provide more specific information about the genetic predisposition to RF in Turkish children.

Acknowledgments. The authors are grateful to the technical cooperation of Mr. Baha (~ifter, Immunology Laboratories of Giilhane Military Medical Academy, Ankara, Turkey.

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Khosroshahi et al.: HLA and Rheumatic Fever

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HLA and rheumatic fever in Turkish Children.

We report the results of research on human leukocyte allo-antigen (HLA) and rheumatic fever (RF), the first published study to be carried out among Tu...
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