Abstract
The use of polymerase chain reaction (PCR) and oligonucleotide hybridization offers a new approach for the definition of HLA class II alleles. It has been possible to determine 43 alleles of DRB1, four of DRB3, two of DRB4, four of DRB5, eight of DQA1, and 14 of DQB1. These alleles are inherited together in members of families and form closely associated groups which are found repeatedly and in characteristics patterns in different populations. We have determined the HLA class II alleles and analyzed their association in 431 healthy unrelated subjects including 161 North American Caucasians, 53 Latin Americans, 61 Blacks, 88 Chinese, and 68 Israeli Jews. For-locus haplotypes (DRB1; DRB3/4/5; DQA1; DQB1) were derived from 79 B cell lines and the analysis of segregation in 34 nuclear families. The B-cell lines yielded 37 and the families showed the same, and 20 other, haplotypic combinations. In addition to these 57 haplotypes, associated alleles were assigned in the unrelated panels following certain rules. The resulting haplotypes were assigned to groups known to share associated alleles. The groups were: (1) DR1, DR2, and DRw10 (13 haplotypes); (2) DR3 and DRw6 (26 haplotypes); (3) DR5 and DRw8 (24 haplotypes); (4) DR4, DR7, and DR9 (24 haplotypes). Their distribution in populations with different ethnic backgrounds was analyzed. The expressed DRB4 allele and its null mutant were determined by PCR and oligonucleotide hybridization. The different DR7 haplotypes resulting from these determinations were analyzed in a panel of 130 North American Caucasoids. This comprehensive analysis of class II HLA haplotypes in human populations should be useful in understanding the role of these genes and in various applications including anthropolgy, disease susceptibility, and transplantation of allogeneic organs and tissues.
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References
Abe, A., Ito, I., Ohkubo, M., Kaneko, T., Ito, K., Kato, H., Kashiwagi, N., and Obata, F.: Two distinct subtypes of the HLA DRw12 haplotypes in the Japanese population detected by nucleotide sequence analysis and oligonucleotide genotyping. Immunogenetics 30: 422–426, 1989
Berte, C. C., Tanigaki, N., Tosi, R., Gorski, J., and Mach, B.: Serological recognition of HLA DR allodeterminant corresponding to DNA sequence involved in gene conversion. Immunogenetics 27: 167–173, 1988
Bodmer, J., Marsh, S., Parham, P., Erlich, H., Albert, E., Bodmer, W., Dupont, B., Mach, B., Mayr, W., Sasazuki, T., Schreuder, G., Strominger, J., Svejgaard, A., and Terasaki, P.: Nomenclature for factors of the HLA system, 1989. Tissue Antigens 35: 1–8, 1990
Braunstein, N. S. and Germain, R. N.: Allele specific control of Ia molecule surface expression and conformation: implications for a general model of Ia structure function relationships. Proc Natl Acad Sci USA 84: 2921–2925, 1987
Demopulos, J. T., Hodge, T. W., Wooten, V., and Acton, R. T.: A novel DRB1 allele in DR2 positive American BLacks. Hum Immunol 30: 41–44, 1991
Fernandez-Viña, M. A., Shumway, W., and Stastny, P.: DNA typing for class II HLA antigens with allele specific or group specific amplification. II. Typing for alleles of the DRw52 associated group. Hum Immunol 28: 51–64, 1990a
Fernandez-Viña, M. A., Fink, C. W., and Stastny, P.: HLA antigens in juvenile arthritis: pauciarticular and polyarticular juvenile arthritis are immunogenetically distinct. Arthritis Rheum 33: 1787–1795, 1990b
Flomenberg, N.: Assignment of T cell defined (TCD) HLA Class II specificities for the reference panel of B-lymphoblastoid cell lines. In B. Dupont (ed.): Immunobiology of HLA Vol I: Histocompatibility Testing 1987, pp. 46–48, Springer, New York, 1989a
Flomenberg, N.: Functional polymorphisms of HLA Class II gene products detected by T-lymphocyte clones: Summary of the Tenth International Histocompatibility Workshop cellular studies. In B. Dupont (ed.): Immunobiology of HLA Vol I: Histocompatibility Testing 1987, pp. 532–550, Springer, New York, 1989b
Gao, X., Fernandez-Viña, M. A., Shumway, W., and Stastny, P.: DNA typing for class II HLA antigens with allele specific or group specific amplification. I. Typing for subsets of HLA DR4. Hum Immunol 27: 40–50, 1990
Gao, X., Moraes, J. R., Miller, S., and Stastny, P.: DNA typing for Class II HLA antigens with allele specific or group specific amplification. V. Typing for subsets of HLA DR1 and Dr'Br'. Hum Immunol 30: 147–154, 1991 a
Gao, X., Sun, Y., An, J., Fernandez-Viña, M. A., Qou, J., Lin, L., and and Stastny, P.: DNA typing for HLA-DR-DQ, and-DP alleles in a Chinese population using the polymerase chain reaction (PCR) and oligonucleotide probes. Tissue Antigens, in press, 1991b
Gorski, J.: The HLA-DRw8 lineage was generated by a deletion in the DR B region followed by first domain diversification. J Immunol 142: 4041–4045, 1989
Gorski, J. and Mach, B.: Polymorphism of human Ia antigens: gene conversion between two DR beta loci results in a new HLA D/DR specificity. Nature 322: 67–70, 1986
Gregersen, P. K., Kao, H., Nunez-Roldan, A., Hurley, C. K., Karr, R. W., and Silver, J.: Recombination sites in the HLA class II region are haplotype dependent. J Immunol 141: 1365–1386, 1988
Gustafsson, K., Wiman, K., Emmoth, E., Larhammar, D., Bohme, J., Hyldig-Nielsen, J. J., Ronne, H., Peterson, P. A., and Rask, L.: Mutations and selection in the generation of class II histocompatibility antigen polymorphism. EMBO J 3: 1655–1661, 1984
Gyllensten, U. B. and Erlich, H. A.: Generation of single stranded DNA by the polymerase chain reaction and its application to direct sequencing of the HLA DQA locus. Proc Natl Acad Sci USA 85: 7652–7656, 1988
Horn, G. T., Bugawan, T. L., Long, C. M., Manos, M. M., and Erlich, H. A.: Sequence analysis of HLA class II genes from insulin dependent diabetic individuals. Hum Immunol 21: 249–263, 1988a
Horn, G. T., Bugawan, T. L., Long, C. M., and Erlich, H. A.: Allelic sequence variation of the HLA DQ loci: Relationship to serology and to insulin dependent diabetes susceptibility. Proc Natl Acad Sci USA 85: 6012–6016, 1988b
Hurley, C. K., Gregersen, P., Steiner, N., Bell, J., Hartzman, R., Nepom, G., Silver, J., and Johnson, A. H.: Polymorphism of the HLA D region in American Blacks. A DR3 haplotype generated by recombination. J Immunol 140: 885–892, 1988
Hurley, C. K., Gregersen, P. K., Gorski, J., Steiner, N., Robbins, F. M., Hartzman, R., Johnson, A. H., and Silver, J.: The DR3(w18), DQw4 haplotype differs from DR3 (w17), DQw2 haplotypes at multiple class II loci. Hum Immunol 25: 37–50, 1989
Hurley, C. K., Lee, K. W., Mickelson, E., Masewicz, S., and Johnson, A. H.: DRw8 microvariation: A new DRB1 allele identified in association with DQw7 in American Blacks. Hum Immunol 31: 109–113, 1991
Inoko, H., Tsuji, K., Groves, V., and Trowsdale, J.: Mapping of HLA Class II genes by pulsed field gel electrophoresis and size polymorphism. In B. Dupont (ed.): Immunobiology of HLA Vol II: Immunogenetics and Histocompatibility, pp. 83–86, Springer, New York, 1989
Knowles, R. W.: Assignment of HLA-Class II alpha and beta Chain 2-D gel patterns for the workshop rreference panel of B-lymphoblastoid cell lines. In B. Dupont (ed.): Immunobiology of HLA Vol I: Histocompatibility Testing 1987,pp. 44–46, Springer, New York, 1989
Knowles, R. W., Flomenberg, N., Horibe, K., Winchester, R., Radka, S. F., and Dupont, B.: Complexity of the supertypic HLA DRw53 specificity: two distinct epitopes differentially expressed on one or all of the DR beta chains depending on the HLA DR allotype. J Immunol 137: 2618–2626, 1986
Lafuse, W. P. and David, C. S.: Recombination hot spots within the I region of the mouse H 2 complex map to the E beta and E alpha genes. Immunogenetics 24: 352–360, 1986
Larhammar, D., Servenius, B., Rask, L., and Peterson, P. A.: Characterization of an HLA-DR beta pseudogene. Proc Natl Acad Sci USA 82: 1475–1479, 1985
Lee, B. S., Bell, J. I., Rust, N. A., and McDevitt, H. O.: Structural and functional variability among DQ β alleles of DR2 subtypes. Immunogenetics 26: 85–91, 1987
Lee, K. W., Johnson, A. H., and Hurley, C. K.: Two divergent routes of evolution gave rise to the DRw13 haplotypes. J Immunol 145: 3119–3125, 1990
Liu, C. P., Bach, F. H., and Wu, S. K.: Molecular studies of a rare DR2/LD 5a/DQw3 HLA class II haplotype. Multiple genetic mechanisms in the generation of polymorphic HLA class II genes. J Immunol 140: 3631–3639, 1988
Mattiuz, P. L., Ihde, D., Piazza, A., Cepellini, R., and Bodmer, W. F.: New approaches to the population genetic and segregation analysis of the HL-A system. In P. I. Terasaki (ed.): Histocompatibility Testing 1970, pp. 193–206, Williams & Wilkins, Baltimore, 1970
Mickelson, E., Reinsmoen, N., Robbins, F. M., Hartzma, R., Odum, N., Svejgaard, A., Farrell, C., Honeyman, M., Flomenberg, N., Sell, T., and Eckels, D.: HLA-Dw and HLA-DP typing of the reference panel of B-lymphoblastoid cell lines. In B. Dupont (ed.): Immunobiology of HLA Vol I: Histocompatibility Testing 1987, pp. 38–42, Springer, New York, 1989
Milford, E. L., Kennedy, L. J., Yang, S. Y., Dupont, B., Lalouel, J.-M., and Yunis, E. J.: Serologic characterization of the reference panel of B-lymphhoblastoid cell lines for factors of the HLA system. In B. Dupont (ed.): Immunobiology of HLA Vol I: HistocompatibilityTesting 1987, pp. 19–38, Springer, New York, 1989
Miller, S. A., Dykes, D. D., and Polesky, H. F.: A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16: 1215, 1988
Moraes, M. E., Fernandez-Viñas, M. A., and Stastny, P.: DNA typing for class II HLA antigens with allele specific or group specific amplification. IV. Typing for alleles of the HLA DR2 group. Hum Immunol 31: 139–144, 1991
Obata, F., Abe, A., Ohkubo, M., Ito, I., Kaneko, T., Otani, F., Watanabe, K., and Kashiwagi, N.: Sequence analysis and oligonucleotide genotyping of HLA DR“JX6”, a DR“blank” haplotype found in the Japanese population. Hum Immunol 27: 269–284, 1990
Petersdorf, E. W., Griffith, R. L., Erlich, H. A., Mickelson, E. M., Smith, A. G., Nisperos, B. B., Martin, P. J., and Hansen, J. A.: Unique sequences for two HLA-DRB1 genes expressed on distinct DRw6 haplotypes. Immunogenetics 32: 96–103, 1990
Reinsmoen, N. L., Layrisse, Z., Betuel, H., Freidel, A. C., and Bach, F. H.: A study of HLA DR2 associated HLA Dw/LD specificities. Hum Immunol 11: 105–115, 1984
Saiki, R. K., Bugawan, T. L., Horn, G. T., Mullis, K. B., and Erlich, H. A.: Analysis of enzymatically amplified beta globin and HLA DQ alpha DNA with allele specific oligonucleotide probes. Nature 324: 163–166, 1986
Scharf, S. J., Friedmann, A., Brautbar, C., Szafer, F., Steinman, L., Horn, G., Gyllensten, U., and Erlich, H. A.: HLA class II allelic variation and susceptibility to pemphigus vulgaris. Proc Nat Acad Sci USA 85: 3504–3508, 1988
Simons, M. J., Wheeler, R., Cohen, D., Lalouel, J.-M., and Dupont, B.: Restriction fragment length polymorphism of HLA genes: Summary of the Tenth International Workshop Southern blot analysis. In B. Dupont (ed.): Immunobiology of HLA Vol I: Histocompatibility Testing 1987, pp. 959–1026, Springer, New York, 1989
Stranick, K. S., Kienzle, B. K., and Knowles, R. W.: Molecular Analysis of a recombination breakpoint in the HLA DQ region. (Abstract). Hum Immunol (Suppl) 29: 6, 1990
Sutton, V. R., Kienzle, B. K., and Knowles, R. W.: An altered splice site is found in the DRB4 gene that is not expressed in HLA DR7, Dw11 individuals. Immunogenetics 29: 317–322, 1989
Sutton, V. R. and Knowles, R. W.: An aberrant DRB4 null gene transcript is found that could encode a novel HLA-DR β chain. Immunogenetics 31: 112–117, 1990
Todd, J. A., Bell, J. I., and McDevitt, H. O.: HLA DQ beta gene contributes to susceptibility and resistance to insulin dependent diabetes mellitus. Nature 329: 599–604, 1987
Tosi, R., Tanigaki, N., Sorrentino, R., Centis, D., and Ferrara, G. B.: Serologically detectable polymorphism of the HLA DC alpha subunit. J Immunol 132: 277–282, 1984
Wu, S., Saunders, T. L., and Bach, F. H.: Polymorphism of human Ia antigens generated by reciprocal intergenic exchange between two DR beta loci. Nature 324: 676–679, 1986
Yang, S. Y., Milford, E., Hammerling, U., and Dupont, B.: Description of the reference panel of B-lymphoblastoid cell lines for factors of the HLA system: The B-cell line panel designed for the Tenth International Histocompatibility Workshop. In B. Dupont (ed.): Immunobiology of HLA Vol I: Histocompatibility Testing 1987, pp. 11–19, Springer, New York, 1989
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Fernandez-Viña, M.A., Gao, X., Moraes, M.E. et al. Alleles at four HLA class II loci determined by oligonucleotide hybridization and their associations in five ethnic groups. Immunogenetics 34, 299–312 (1991). https://doi.org/10.1007/BF00211994
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DOI: https://doi.org/10.1007/BF00211994