HLA-DR6 (possibly DRB1*1301) is associated with susceptibility to Takayasu arteritis in Mexicans

HLA-DR6 (possibly DRB1*1301) is associated with susceptibility to Takayasu arteritis in Mexicans
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  Originals Heart andVessel s © Springer-Verlag 996 Heart Vessels (1996) 11:277-280 HLA-DR6 possibly DRBI*1301) is associated with susceptibility to Takayasu arteritis in Mexicans Eduardo Girona 1, Jesüs K. Yamamoto-Furusho 2, Teresa Cutifio 1, Pedro Reyes 1, Gilberto Vargas-Alarcón 2, Julio Granados 2, and Donato Alarcón-Segovia 2 i Department of Immunology, Instituto Nacional de Cardiologia Ignacio Chävez, Mexico 2Department of Immunology and Rheumatology, Instituto Nacional de la Nutrición Salvador Zubirän, Vasco de Quiroga 15, Tlalpan 14000, México, D.F., México Summary. Takayasu arteritis is characterized by a ùpulseless condition and occurs frequently in young females from Asian and South American countries. This disease has been found to be linked with major histocompatibility complex (MHC) antigens in Japa- nese individuals. In the present study we compared gene frequencies of class I, class II, and class III MHC genotypes in patients with Takayasu arteritis and ethni- cally matched healthy controls. Serological typing was confirmed by molecular typing at the DNA level. We found significant increases in the frequencies of human leucocyte antigen (HLA)-DR6 and HLA-B62 in pa- tients compared to the healthy controls (P corrected [C] = 0.0007, relative risk IRR] = 5.08; PC = 0.05, RR = 3.13 respectively). However, since the number of patients was considerably lower than the number of controls this can be considered as a tendency and not a true association. On the other hand, we found a significantly decreased frequency of HLA-DR4 in pa- tients compared to healthy controls (PC = 0.04, RR = 0.34). At the DNA level, all DR6-positive individuals were HLA-DRB1*1301 whereas controls were HLA- DRBl*1301 (4.2%). Takayasu arteritis in Mexicans is probably associated with the HLA-DR6 (DRBl*1301) gene. Key words: Major histocompatibility complex (MHC) - HLA antigens - Takayasu arteritis Address correspondence to: J. Granados Received September 25, 1996; revised December 9, 1996; accepted January 10, 1997 Introduction Takayasu arteritis is a form of vasculitis with the characteristic feature of being a pulseless condi- tion ( pulseless disease ) due to obstruction of the arteries, mainly the aortic arch, its main branches, and the abdominal aorta [1-3]. This disease is more common in Asian individuals than in other ethnic groups. It affects females more frequently than males and varies in its clinical presentation, from asympto- matic to catastrophic. Patients show a heterogeneous response to treatment with glucocorticoids and cyto- toxic agents [4]. Genetic susceptibility to Takayasu arteritis has been reported to be associated with the major histocompatibility complex (MHC) haplotype human leucocyte antigen (HLA)-B52, DRBI*1502, DRB5*0102, DQAI*0103, DQBI*0601, DPA1*02, DPBI*0401 in Japanese patients [5-6]. A comparative study conducted in three Asian countries revealed differences between Indian, Korean, and Japanese patients in the localization of the aortic lesion, complications, and causes of death. Nevertheless, HLA-B52 or B5 was related to Takayasu arteritis in all three of these Asian countries [7]. These results suggest that genetic factors are involved in the patho- genesis of the disease, and that they are probably located between the HLA-B and HLA-D loci within the short arm of the sixth chromosome [8]. In fact, patients carrying this haplotype were found to have an increase in the inflammatory state and to exhibit a rapid progression of this morbid condition when compared to patients not carrying this haplotype [9]. Takayasu arteritis has also been found in Mexican Mestizos, an ethnic group in whom 56% of their gene pool is of Amerindian srcin, this being clearly related to the Mongolian racial group from which Amerindians are believed to have srcinated 50000 years ago. In this study, we investigated whether genetic markers  278 E. Girona et al.: HLA-DR6 is associated with susceptibility to Takayasu arteritis in Mexicans in Mexican patients differ ffom those already described in oriental patients. BF*S, C2 C, C4A'3, and C4B'1 alleles, and com- plotype FC31 represents the BF*F, C2 C, C4A'3, and C4B*I alleles. Patients and methods Patients We studied 12 Mexican Mestizo patients who attended the Cardiology Outpatient Clinic at the Instituto Nacional de Cardiologfa, in Mexico City. All patients were women, with ages ranging from 18 to 27 years (mean, 22.5 years). The diagnosis of Takayasu arteritis was based on clinical assessment, laboratory tests, and aortic angiography. To analyze the MHC haplotypes, we also studied some of their first-degree relatives (par- ents and siblings). Controls The study was performed in 50 ethnically matched fami- lies, all of whom included both parents, and with an average of five children per family. The results were based on 200 haplotypes, as only the 100 parents were considered for analysis. All subjects, their parents, and grandparents were of Mexican ancestry, with the major- ity born in Mexico City. The inclusion criteria were: (a) both parents had to be available; (b) Mexican ancestry up to the grandparents was required; (c) none of the tested individuals were known to suffer from any HLA- associated diseases [10]. HLA typing Venous blood samples were obtained from the patients and controls. Lymphocytes were isolated from peri- pheral blood, using a density gradient centrifugation technique [11], and B cells were separated with Lympho-Kwik reagent One Lambda, CA, USA). The mononuclear cells were subjected to HLA-A, -B, and -C typing with a standard microcytotoxicity test [12- 14], while HLA-DR and HLA-DQ typing was per- formed on the B cells, using a similar technique, but with prolonged incubation times [14]. Typing trays were purchased from Pel-Freez (Brown Deer, Wis. USA) and contained a total of 210 antisera: 140 to define 40 specificities from HLA-A, -B, and -C loci and 70 to define 18 specificities from the HLA-DR and DQ loci. Class III genes were determined by high- voltage agarose gel electrophoresis and immuuofixation with specific antibodies [15]. The nomenclature for class III genes has been published elsewhere [16-18]. Thus, the term complotype means the comple- ment haplotype and refers to the MHC class III genes. Accordingly, the complotype SC31 represents the Statistical analysis Mantel-Haenszel k z analysis was performed to deter- mine the significance of differences between the two groups. This anälysis was combined with the 2 × 2 tables using the EPISTAT statistical program. If the number in any cell was less than five, Fisher's exact test was used. The P values were corrected by multiplying by the number of comparisons. Relative risks (RR) were calculated by Woolf's method. Results Table 1 shows the complete MHC haplotypes of the 12 patients with Takayasu arteritis. Six of these patients were positive for the HLA-DR6 antigen, which is more commonly seen as part of the HLA-DR13-B49 haplotype, and one of them was homozygous for DR13 but not for HLA-B49 (patient 5). The other 5 patients were either DR4- or DR7-positive as part of either the HLA-B39 or -B35 haplotypes, (patient 9 was B35 ho- mozygous). The remaining patient (patient 12) had the HLA-DR3-SC01-B8 haplotype and the other haplotype was HLA-B5 positive. All patients who were DR6- positive showed the DRBl*1301 allele. No difference was found between patients and con- trols at the HLA-A locus, the most common alleles being A2 and A31 in both groups (Table 2). At the HLA-B locus, B39 was the most common allele found in the patients. However, it was present at almost the same frequency in controls. Although B62 was not the most common allele in the patients, it showed a significant difference in frequency compared to the controls (PC = 0.05, RR = 3.13). At the HLA-DR locus, subspecificities were grouped with their main al- lele specificities, e.g., HLA-DR5 included DRll and DR12 and HLA-DR2 included DR15 and DR16; in most DR6-positive patients DR6 was associated with DRBl*1301, and HLA-DR3 was associated with DR17 in all patients with HLA-DR3. Analysis of the gene frequencies showed that DR6 (DRBl*1301) was the most frequent allele in patients, and was significantly different compared to the controls (PC = 0.0007, RR = 5.08). However, this was not a true association, since the number of patients was considerably lower than the number of controls. An outstanding finding was the significant decrease in frequency of DR4 in the patient group, compared to the controls (P = 0.04, RR = 0.34). At the DQ locus, the distribution of alleles in patients and controls was identical.  E. Girona et al.: HLA-DR6 is associated with susceptibility to Takayasu arteritis in Mexicans Table 1. Class I, II, and III MHC haplotypes in Mexican patients with Takayasu arteritis 279 Patient number Maternal chromosome Paternal chromosome HLA C* HLA C* 1. A31 B49 SC31 DR13 DQ1 A28 B62 SC42 DR1 DQ1 2. A31 B39 SC33 DR13 DQ1 A31 B44 FC31 DR7 DQ2 3. A2 B70 SC31 DR14 DQ3 A2 B39 SC30 DR4 DQ3 4. A2 B49 SC30 DR13 DQ1 A1 B44 SC33 DR7 DQ2 5. A3 B49 SC32 DR13 DQ1 A28 B39 FC30 DR13 DQ1 O. A24 B18 SC30 DR13 DQ1 A25 B42 FC51 DR8 DQ3 7. A24 B39 SC31 DR4 DQ3 A28 B62 SC42 DR8 DQ3 8. A2 B62 SC52 DR4 DQ3 All B60 SC31 DR8 DQ3 9. A24 B35 SC31 DR4 DQ3 A25 B35 SC31 DR2 DQ3 10. A3 B39 SC42 DR7 DQ2 A1 B60 SC61 DR9 DQ3 11. A3 B18 SC30 DR6 DQ1 A10 B42 FC51 DR8 DQ3 12. A31 B51 SC31 DR7 DQ2 A2 B62 SC31 DR5 DQ3 C*, Complotype, i.e., complement haplotypes; refers to MHC class III genes. Accordingly, the SC31 complotype represents the BF*S, C2 C, C4A'3 and C4B'1 alleles. Likewise, complotype FC31 represents the BF*F, C2 C, C4A'3, C4B'1 alleles MHC, Major histocompatibility complex Table 2. Gene frequencies of HLA class I and class II in Mexican patients with Takayasu arteritis HLA Patients Controls (n = 24) (n = 200) gf gf PC RR A2 0.208 0.280 NS - A31 0.208 0.200 NS - A24 0.125 0.160 NS - A28 0.125 0.120 NS - B39 0,208 0,150 NS - B62 0.166 0.060 0.05 3.13 B49 0.125 0,045 NS - B44 0.083 0.960 NS - DR6 0.291 0.075 0.0007 5.08 DR7 0.166 0.065 NS - DR4 0.166 0.370 0.04 0.34 DR2 0.041 0.075 NS - DR3 0.041 0.070 NS - DR5 0.041 0.110 NS - DQ1 0.333 0.220 NS - DQ2 0.208 0.125 NS - DQ3 0.458 0.600 NS - PC, PCorrected; NS, non-significant; RR, relative risk; gf, gene frequency; HLA, human leucocyte antigen Discussion This study shows the direct role played by MHC class II genes, particularly the allele HLA-DR6 (DRBl*1301), in susceptibility to Takayasu arteritis. This study was conducted in families, to obtained MHC haplotypes, and showed no significant differences in haplotypes be- tween patients and controls. Typing at the DNA level showed that all DR6- positive individuals had the HLA-DRBI*1301 allele (25 %), whereas healthy controls had HLA-DRB 1 1301 (4.2%). These results differ from those obtained in dif- ferent ethnic groups, mainly in Oriental populations, where the existence of the HLA-B52-DRB1*1502- DRB5*0102-DQAl*0103-DQBl*0601-DPAl*02- DPB1*0401 haplotype has been reported previously [5, 6]. Interestingly, none of the Mexican patients showed this haplotype, a finding that suggests that genetic sus- ceptibility is influenced by ethnicity. Takayasu arteritis is rare world-wide, except for Ori- ental populations; in Mexicans, also, it does not seem to be uncommon. The finding of different MHC alleles in Mexican patients compared to those in Orientals would suggest the strong influence of ethnicity in each of these ethnic groups. However, the mechanism that trig- gers the susceptibility could be the same, and infec- tious agents seem to be good candidates; indeed, anti- gens from Mycobacterium tubercu osis appear to be involved. Certainly, the HLA-B alleles, B52, B39, and B62, may share nucleotide sequences related to the disease. These shared sequences may also be present in Mexi- cans. Indeed, the results of this study suggest that HLA- B62 and HLA-DR6 seem to have independent roles in the genetic susceptibility to Takayasu arteritis. In conclusion, although Takayasu arteritis seems to be clinically and genetically heterogeneous, the MHC genes probably exert a direct influence on susceptibility to this disease. References 1. Caccamise WC, Whiteman JF (1952) Pulseless disease. A preliminary case report. Am Heart J 44:629-633 2. Ishikawa K (1978) Natural history and classification of acclusive thromboaortopathy. Circulation 57:27-34 3. Shimizu K, Sano K (1951) Pulseless disease. J Neuropath Exp Neurol 1:37-42  280 E. Girona et al.: HLA-DR6 is associated with susceptibility to Takayasu arteritis in Mexicans 4. Kerr GS, Hallajan CW, Giordano J, Leavitt RY, Fauci AS, Rottem M, Hoffman GS (1994) Takayasu arteritis. Ann Intern Med 120:919-929 5. Dong RP, Kimura A, Numano F, Yajima M, Hashimoto Y, Kishi Y, Nishimura Y, Sasazuki T (1992) HLA-DP antigen and Takayasu arteritis. Tissue Antigens 39:106- 110 6. Dong RP, Kimura A, Numano F, Nishimura Y, Sasazuki T (1992) HLA-linked susceptibility and resistance to Takayasu arteritis. Heart Vessels [Suppl] 7:73-80 7. Yajima M, Numano F, Park YB, Sagar S (1994) Compara- tive studies of patients with Takayasu arteritis in Japan, Korea and India - comparison of clinical manifestations, angiography and HLA-B antigen. Jpn Circ J 58:9-14 8. Back Fh, Van Rood JJ (1976) The major histocompatibil- ity complex: Genetics and biology. N Engl J Med 295:806- 813,872-878 9. Numano F, Otha N, Sasazuki T (1982) HLA and clinical manifestations in Takayasu disease. Jpn Circ J 46:184-189 10. Weckman AL, Vargas-Alarcón G, López M, Gonzälez N, De Leo C, Castelan N, Bordes J, Alarcón-Segovia D, Granados J, Ramffez E, Lisker R (1997) Frequency of HLA-A and HLA-B alleles in a Mexico City Mestizo group. Am J Hum Biol 9:1-5 11. Boyum A (1968) Isolation of leukocytes from human blood: Further observations. Scand J Clin Lab Invest Suppl 97:31 12. Terasaki PI, Bernoco DD, Park MS, O'Zturk G, Iwaki Y (1978) Microdroplet testing for HLA-A, B, C, and D an- tigens. Am J Clin Pathol 69:103-120 13. Terasaki PI, McClelland JD (1964) Microdroplet assay of human serum cytotoxins. Nature 204:998 14. Bodmer JG, Pickbourne P, Richards S (1977) Ia serology. In: Bodmer WF, Batchelor JR, Bodmer JG, Festenstein H, Morris PJ (eds) Histocompatibility testing. Munksgaard, Copenhagen, p 35 15. Alper CA, Boenisch T, Watson L (1972) Genetic poly- morphism in human glycine-rich betaglycoprotein. J Exp Med 135:68-80 16. Alper CA, Raum D, Karp S (1983) Serum complement supergenes on the major histocompatibility complex in man (complotypes). Vox Sang 45:62 17. Awdeh ZL, Alper CA (1980) Inherited structural poly- morphism of the fourth component of human comple- ment. Proc Natl Acad Sci USA 77:3576-3580 18. Alper CA (1976) Inherited structural polymorphism in human C2: Evidence for linkage between C2 and BF. J Exp Med 144:1111-1115
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