Heart Vessels (1992) Suppl. 7:81-84

Heart

aWessels

© Springer-Verlag1992

HLA Typing of Takayasu arteritis in Korea Myoung Hee Park ~and Young Bae Park 2 1Department of Clinical Pathology and 2Department of Internal Medicine, Seoul National University College of Medicine, 28 Yongondong, Chongnogu, Seoul 110-744, Korea

Summary. Takayasu arteritis occurs with a strong predilection for women and particular geographic areas, and as related to the etiology of the disease, association of H L A antigens has been suggested. In the present study, the authors investigated the association of Takayasu arteritis with class I and class II H L A antigens in 59 Korean patients with this disease. Increased frequencies of HLA-Bw52 (;(2 6.213, P < 0.02), Cw6 (;(2 4.132, P < 0.05), DR7 (;(2 4.506, P < 0.04), and DQw2 (;(; 7.327, P < 0,01) were observed in the patient group as compared to the control group of healthy Koreans. In the Korean population, 2 risk factors in the H L A system for developing this disease appear to be (1) Bw52 and (2) DR7 and a probable haplotype of Cw6, B13, DR7, DQw2. Previous studies of the Japanese population revealed association of Bw52 and class II H L A antigens (DR2, Dw12), which are in linkage disequilibrium with Bw52. It is of interest that in the Korean population, class II antigens (DR7, DQw2), which are not linked to BW52, are associated with the disease. This finding suggests that the disease susceptibility gene of Takayasu arteritis is located between the H L A - B locus and H L A - D R , DQ loci.

Key words: Takayasu arteritis - H L A - Korean

[2, 4]. A strong predilection for women and high incidence in Asian or South American countries suggest the etiologic role of genetic factors [2, 3]. In relation to the participation of genetic factors in the cause of the disease, association of particular H L A antigens have been reported, mostly for Ja panese populations. Increased incidence of HLA-Bw52 antigen is general in Japanese patients [5-9]. Increased incidence of HLA-Dw12 (DHO) [5-8] and H L A - D R 2 [9] was also reported in Japanese patients, which shows linkage disequilibrium with HLA-Bw52 in the Japanese population [10]. There are few reports outside Japan. Association of HLA-B5 and HLA-B21 was suggested in Indian patients with this disease [11]. Volkman and coworkers [12] reported possible assoc i a t i o n of DR4 and DQw3 (MB3) in a study of 11 patients of varying ethnic backgrounds (8 Caucasian, 2 Korean, 1 mixed). To elucidate possible association of H L A antigens and Takayasu arteritis in the Korean population, 59 patients were studied for class I and class II H L A antigens. It is of interest that in addition to HLABw52, the incidences of HLA-Cw6, DR7 and DQW2 were increased in Korean patients with this disease. It is suggested that the disease susceptibi|ity gene of Takayasu arteritis is located between the I t L A - B region and H L A - D region genes.

Materials and methods Introduction Takayasu arteritis is a chronic vasculitis of unknown etiology with the characteristic feature of "pulselessness" [1-3]. The vasculitis occurs segmentally in the aorta, its main branches, and the pulmonary artery

Address correspondence to: M.H. Park

Fifty-nine patients with Takaysu arteritis seen in the Department of Internal Medicine of Seoul National University Hospital were studied. Diagnosis of the disease was based on clinical features and arteriographic findings. The presence of multiple stenotic or dilated lesions of the aorta, its main branches, and/or pulmonary arteries, with no detectable specific causes of the arterial lesion was considered as diagnostic. The patients included 50 females and 9 males, aged 16-58 years (mean 32.6) at the time of study. One hundred healthy Koreans served as controls.

M.H. Park and Y.B. Park: HLA Typing of Takayasu arteritis in Korea

82

HLA-A, B, C, DR, and DQ antigens were typed by standard microlymphocytotoxicity test [13]. Commercial antisera trays (One Lambda Co., USA) were used for serologic typing of class I and class Il antigens and the antigenic assignments were based on the nomenclature for factors of the HLA system, 1987 [14]. A statistical analysis was performed using the z2-test of antigens in association with this disease, with Fisher's exact test applied when appropriate.

Results Tables 1, 2, and 3 show the H L A antigen frequencies in patients with Takayasu arteritis and controls of healthy Koreans. H L A antigens, significantly higher in the patient group as compared to the control group, were Cw6 (31.6% vs 16%, RR 2.42, Z2 4.132, P < 0.05), Bw52 (18.6% vs 6%, R R 3.59, Z2 6.213, P < 0.02), DR7 (30.5% vs 16.2%, RR 2.28, ;Ü 4.506, P < 0.04) and DQw2 (40.5% vs 18.2%, RR 3.07, ;~2 7.327, P < 0.01). Analysis of combination of antigens involving DR7 showed increased frequency of Cw6, B13, DR7 (probable haplotype) in the patient group as compared to the control group (23.7% vs 9.1%, R R 3.10, Z2 5.124, P < 0.03), however B44, DR7 (probale haplotype) was not significantly different between the 2 groups (11.9% vs 8.1%).

Discussion The etiology of Takayasu arteritis remains obscure. Epidemiological studies carried out in Japan in 1975 [1] )evealed that 89% of all patients were females and

we had a similar figure of 85% of the patients being females in this study. This disease most offen occurs in Asian or South American countries, with very few incidences in western countries [2,3]. At least 10 family cases have been reported and genetic factors were suggested to be involved in disease pathogenesis [151. Association of H L A antigens with Takayasu arteritis have been reported, mostly for the Japanese populations (Table 4). Previous studies have indicated the association of this disease with Bw52 [5-9], Dwl2 (DHO) [5-8], DR2 [9], and D Q w l [9] specificities. A recent study, regarding H L A - D Q A polymorphism at the genomic level revealed the association of this disease with Taq-I generated H L A - D Q A restriction fragment of 6.6 kb size [16]. Among these specificities, association of Bw52 is most consistently found with relatively high levels of relative risk and Z2 value. Moriuchi et al. [9] reported the significant association of DR2/DQwl (MB1) with this disease, whereas Numano et al. [17] denied their association. It is well known that Dw12 and DR2 are positively linked to Bw52 in the Japanese population [10]. In a recent study [18], it was also demonstrated that Taq I-DQA 6.6kb was highly associated with H L A - D w l 2 and Bw52 in the Japanese population. Thus, the association of HLA-Dwl2, DR2 and Taq I-DQA 6.6kb with Takayasu arteritis appear to be secondary to that with Bw52. It is of interest that in this study of the Korean population, we found the association of Cw6, DR7, and DQw2 with this disease, in addition to that of Bw52. The antigen frequency of DR7 is significantly higher in healthy Koreans (16% [19], 16.2% in this

Table 1. HLA-A and HLA-C Antigens in patients with Takayasu arteritis Antigen

Patient (n = 59)

Control (n = 100) Relative risk Chi square P value

A1 A2 A3 All A24 A26 A29 A30 A31 A32 Aw33

2 (3.4%) 31 (52.5%) 2(3.4%) 8 (13.6%) 16 (27.1%) 7 (11.9%) 2(3.4%) 9 (15.3%) 7 (11.9%) 0( 0%) 17 (28.8%)

9 (9%) 55 (55%) 1 (1%) 15 (15%) 36 (36%) 11 (11%) 1 (1%) 9 (9%) 8 (8%) 1 (1%) 33 (33%)

0.35 0.91 3.47 0.89 0.66 1.09 3.47 1.82 1.55

Cwl Cw2 Cw3 Cw4 Cw6 Cw7 Cw8 Cw11

9 (15.3%) 0( 0%) 25 (42.4%) 6 (10.2%) 12 (31.6%) a 7 (18.4%) a 2 (5.3%) a 1(2.6%) a

23 (23%) 2 (2%) 47 (47%) 12 (12%) 16 (16%) 23 (23%) 4 (4%) 8(8%)

0.60

an = 38 NS, Not significant, P > 0.05

0.82

0.83 0.83 2.42 0.76 1.33 0.31

1.814 0.090 1.145 0.062 1.330 0.028 1.145 1.446 0.649 0.594 0.302

NS NS NS NS NS NS NS NS NS NS NS

1.385 1.195 0.321 0.124 4.132 0.339 0.106 1.302

NS NS NS NS 0.05

study) compared to an extemely low frequency in Japanese (0.9%) [20]. In Orientals, D R 7 is associated with D Q w 2 [21], and shows significant linkage disequilibria with B13 and Cw6 [22]. In Koreans, D R 7 shows significant linkage disequilibria with Cw6 [19].

B12 (B44) [19, 20], and B13 [19, 20]. Analysis of combinations of antigens involving DR7 showed the association of Cw6, B13, DR7 (probable haplotype), but not of B44, DR7, with this disease. Thus, two risk factors of HLA system for developing Takayasu

M.H. Park and Y.B. Park: HLA Typing of Takayasu arteritis in Korea

84

Table 4. Association of HLA antigens with Takayasu arteritis HLA Antigen

Population

Patient

Control

n

%+

n

%+

Relative risk

Chi square

Reference

HLA-Bw52

Japanese Japanese Japanese Korean

75 82 75 59

44 44 44 19

181 128 128 100

16 13 13 6

4.08 5.14 5.50 3.59

21.37 23.55 25.60 6.21

[6] [5] [7] Authors

HLA-Cw6

Korean

38

32

100

16

2.42

4.13

Authors

HLA-DR2

Japanese Japanese

52 30

46 77

884 51

36 35

1.52 5.85

2.19 12.46

[17] [9]

HLA-DR7

Korean

59

31

99

16

2.28

4.51

Authors

HLA-DQw2

Korean

37

41

99

18

3.07

7.33

HLA-DQA, 6.6 kb a

Japanese

32

66

34

35

3.5

0.07

[16]

HLA-Dw12(DHO)

Japanese Japanese

75 75

40 40

128 181

21 18

2.50 3.02

10.40 13.48

[7] [6]

Authors

aTaq I-generated HLA-DQA restriction fragment

arteritis in the Korean population appear to be (1) Bw52 and (2) D R 7 and a probable haplotype of Cw6, B13, DR7 DQw2. The disease susceptibility gene of Takayasu arteritis is postulated to be located between the HLA-B locus and HLA-DR, DQ loci.

References 1. Committee Report (1975) Clinical and pathological studies of Takayasu's disease. A report by the Ministry of Health and Welfare, Japan 2. Lupi HE, Sänchez TG, Marcushamer J, Horwitz S, Vela JE (1977) Takayasu's arteritis, clinical study of 107 cases. Am Heart J 93:94-103 3. Ishikawa K (1978) Natural history and classification of occlusive thromboaortopathy (Takayasu's disease). Circulation 57:27-35 4. Committee Report (1968) Clinical and pathological studies of aortitis syndrome. Jpn Heart J 9:76-87 5. Isohisa I, Numano F, Maezawa H, Sasazuki T (1978) HLA-Bw52 in Takayasu disease. Tissue Antigens 12: 246-248 6. Sasazuki T, Ohta N, Isohisa I, Numano F, Maezawa H (1979) Association between Takayasu disease and HLADHO. Tissue Antigens 14:177-178 7. Isohisa I, Numano F, Maezawa H, Sasazuki T (1982) Hereditary factors in Takayasu's disease. Angiology 33: 98 - 104 8. Numano F, Ohta N, Sasazuki T (1982) HLA and clinical manifestations in Takayasu disease. Jpn Circ J 46:184189 9. Moriuchi J, Wakisaka A, Aizawa M, Yasuda K, Yokota A, Tanabe T, Itakura K (1982) HLA-linked susceptibility gene of Takayasu disease. Hum Immunol 4:87-91 10. Reinsmoen NE, Sasazuki T, Kaneoka N, Ohta N, Noreen HJ, Greenberg LJ, Kersey JH (1978) Two distinct HLA-D specificities (DHO and Dw2) in linkage with HLA-DRw2 as defined in white and Japanese populations. Transplant Proc 10:789-791

11. Rose S, Mehra NK, Kumar R, Vaidya MC (1991) HLAB5 and B21 antigens in aortoarteritis. Ind J Pediatr 58:85-89 12. Volkman DJ, Mann DL, Fauci AS (1982) Association between Takayasu's arteritis and a B-cell alloantigen in North Americans. New Engl J Med 306:464-465 13. Terasaki PI (1976) Microdroplet lymphocytotoxicity test. In: Ray JG, Hare DB, Pedersen PD (eds) Manual of tissue typing techniques. DHEW publication No. (NIH) 76-545, Bethesda. pp 69-80 14. WHO-HLA Nomenclature Committee (1989) Nomenclature for factors of the HLA system, 1987. Vox Sang 55:119-126 15. Numano F, Isohisa I, Maezawa H, Juji T (1979) HLA antigens in Takayasu's disease. Am Heart J 98:153-159 16. Takeuchi Y, Matsuki K, Saito Y, Sugimoto T, Juji T (1990) HLA-D region genomic polymorphism associated with Takayasu's arteritis. Angiology 4t:421-426 17. Numano F, Isohisa I, Egami M, Ohta N, Sasazuki T (1983) HLA-DR MT and MB antigens in Takayasu disease. Tissue Antigens 21:208-212 18. Matsuki K, Maeda H, Juji T, Inoko H, Ando A, Tsuji K, Honda Y (1988) Taq l-generated HLA-DQ alpha polymorphism in Japanese patients with narcolepsy. Immunogenetics 27:87-90 19. Kim SJ, Nisperos B, Mickelson E, Choi IH, Dahlberg S, Kim JD, Giblett ER, Hansen JA (1986) The HLA system in the Korean population. Hum Immunol 17: 259-272 20. Aizawa M, Natori T, Wakisaka A, Konoda Y (1986) HLA in Asia-Oceania 1986. Hokkaido University Press, Sapporo, pp 1080-1103 21. Schreuder GMT, Doxiadis I, Parlevliet J, Gross-Wilde H (1984) HLA-DR, DQ, LB, and TAl0 specificities of Ninth Workshop homozygous typing cells. In: Albert ED, Bauer MP, Mayr WR (eds) Histocompatibility testing 1984. Springer, Berlin Heidelberg, pp 243-248 22. Bauer MP, Neugebauer M, Albert ED (1984) Reference tables of two-locus haplotype frequencies for all MHC marker loci. In: Albert ED, Bauer MP, Mayr WR (eds) Histocompatibility testing 1984. Springer, Berlin Heidelberg, pp 677-678

HLA typing of Takayasu arteritis in Korea.

Takayasu arteritis occurs with a strong predilection for women and particular geographic areas, and as related to the etiology of the disease, associa...
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