Abstract
From the study of HLA, complement, and glyoxalase I alleles in 82 Venezuelan individuals belonging to 19 families of mixed ethnic origin having 20 affected newborns with salt-wasting congenital adrenal hyperplasia due to 21-hydroxylase (21-OH) deficiency, a total of 38 disease haplotypes and 53 nondisease haplotypes were found. Of the pathological haplotypes 47 % were found to share the HLA-B39 or -Bw62 specificities, 55 % of them in combination with the BFS, C2C, C4A4, C4B2 (SC42) complotype. The frequencies of HLA-B39 and -Bw62 among the affected haplotypes were 29 and 18% as compared with 6 and 0 % among the nondisease haplotypes of the same families. Statistical associations (P < 0.01) with salt-wasting adrenal hyperplasia were found with the SC42 complotype and with the combination SC42, HLA-B39. These results are markedly different from those reported in the literature which show an “association” at the population level among many Caucasoid samples of HLA-Bw47 and the extended haplotype (HLA-Bw47, DR7, FC91, 0) with the salt-wasting form of the disease. Furthermore, four of the unrelated patients reported here were homozygous for all the major histocompatibility complex loci tested, while three others were homozygous for at least two HLA loci. Analysis of the geographical origin of the grandparents indicated clustering of the deficiency carrier HLA haplotypes. This observation, together with the fact that there is an excess of homozygotes among the patients in Venezuela, strongly suggests that salt-wasting 21-OH deficiency congenital adrenal hyperplasia is mostly the result of a founder effect of relatively few independent mutations and, thus, of identity by descent of a few abnormal alleles at the 21-OHB locus in most cases. The mutation marked by HLA-Bw47 was not observed in this population.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Alper, C. A.: Inherited structural polymorphism in human C2: Evidence for genetic linkage between C2 and Bf. J. Exp. Med. 144: 1111–1115, 1976
Alper, C. A., Boenisch, T., and Watson, L.: Genetic polymorphism in human glycine-rich beta-glycoprotein. J. Exp. Med. 135: 68–80, 1972
Arias, S.: Simposio sabre focos de enfennedades monogenicas en Latinoamerica. La experiencia venezolana del Laboratorio de Genetica Humana del IVIC. Proceedings of the VII Latinamerican Congress of Genetics, 1985
Awdeh, Z. L. and Alper, C. A.: Inherited structural polymorphism of the fourth component of human complement (C4). Proc. Natl. Acad. Sci. U.S.A. 77: 3576–3580, 1980
Awdeh, Z. L., Raum, D., and Alper, C. A.: Genetic polymorphism of the fourth component of human complement: Detection of heterozygotes. Nature 282: 205–207, 1979
Black, E: Interrelationships between Amerindian tribes of Lower Amazonia as manifest by HLA haplotype disequilibra. Am. J. Hum. Genet. 36: 1318–1331, 1984
Carroll, M. C., Belt, K. T., Palsdottir, A., and Yu, Y.: Molecular genetics of the fourth component of human complement and steroid 21-hydroxylase. Immunol. Rev. 87: 39–60, 1985
Danilovs, J. A., Ayoub, G., and Terasaki, P. L.: B lymphocyte isolation by thrombin-nylon wool. In P. I. Terasaki (ed.): Histocompatibility Testing 1980, pp. 287–288, UCLA Press, Los Angeles, 1980
Dupont, B., Oberfield, S. E., Smithwick, E. M., Lee, T. D., and Levine, L. S.: Close genetic linkage between HLA and congenital adrenal hyperplasia (21-hydroxylase deficiency). Lancet 2: 1309–1312, 1977
Dupont, B., Pollack, M. S., Levine, I. S., O'Neill, G. J., Hawkins, B. R., and New, M. I.: Joint report. Congenital adrenal hyperplasia. In P. I. Terasaki (ed.): Histocompatibility Testing 1980, pp. 693–706, UCLA Press, Los Angeles, 1980
Fleischnick, E., Raum, D., Alosco, S. M., Gerald, P. S., Yunis, E. J., Awdeh, Z. L., Granados, J., Crigler, J. E., Jr., Giles, C. M., and Alper, C. A.: Extended MHC haplotypes in 21-hydroxylasedeficiency congenital adrenal hyperplasia: Shared genotypes in unrelated patients. Lancet 1: 152–156, 1983
Grosse-Wilde, H., Weil, J., Albert, E., Scholz, S., Bidlingmaier, F., Sippel, W. G., and Knorr, D.: Genetic linkage studies between congenital adrenal hyperplasia and the HLA blood group system. Immunogenetics 8: 41–49, 1979
Kömpf, J., Bissbort, S., Gussmann, S., and Ritter, H.: Polymorphism of red cell glyoxalase I (E. C.: 4.4.1.5): A new genetic marker in man. Humangenetik 27: 141–143, 1975
Layrisse, Z.: Conocimiento actual del sistema HLA enindigenas suramericanos. In J. Vargas Arenas and V. Rodriguez L. (eds.): Memorias del II Congresso Venezolano de Genetica, UCV Press, Caracas, 1985
Layrisse, Z., Rodriguez-Iturbe, B., Garcia-Ramirez, R., Rodriguez, A., and Tiwari, J.: Family studies of the HLA system in acute poststreptococcal glomerulonephritis. Hum. Immunol. 7: 177–185, 1983
Lorenzen, F., Pang, S., New, M. I., Dupont, B., Pollack, M. S., Chow, D. M., and Levine, L. S.: Hormonal phenotype and HLA-genotype in families of patients with congenital adrenal hyperplasia (21-hydroxylase deficiency). Pediatr. Res. 13: 1356–1360, 1979
McCluskey, J., Kay, P. H., Stuckey, M., Christiansen, E. T., Dawkins, R. L., and Wilson, G.: MHC “supratype” predicting heterozygous 21-hydroxylase deficiency. Lancet 1: 765–766, 1983
Pollack, M. S., New, M. L., O'Neil, G. J., Levine, L. S., Callaway, C., Pang, W., Cacciari, E., Mantero, F., Cassio, A., Scaroni, C., Chimuello, G., Rondanini, G. F., Gargantini, L., Giovannelli, G., Virdis, R., Barrolatta, E., Migliori, C., Pintor, C., Tato, L., Barbini, E., and Dupont, B.: HLA genotypes and HLA linked genetic markers in Italian patients with classical 21-hydroxylase deficiency. Hum. Genet. 58: 331–337, 1981
Pollack, M. S., Levine, L. S., Pang, S., Owens, R. P., Nitowsky, H. M., Maurer, D., New, M. I., Duchon, M., Merkatz, I. R., and Sachs, G.: Prenatal diagnosis of congenital adrenal hyperplasia (21-hydroxylase deficiency) by HLA typing. Lancet 1: 1107–1108, 1985
Scholz, S., Holler, W., Knorr, D., Bidlingmaier, F., Zander, H., and Albert, E. D.: Three different HLA associations in the three types of 21-hydroxylase congenital adrenal hyperplasia. In E. D. Albert, M. P. Baur, and W. R. Mayr (eds.): Histocompatibility Testing 1984, pp. 658–659, Springer-Verlag, Berlin, 1984
Sigmund, M.: PEDPLO: The pedigree plot program. In E. D. Albert, M. P. Baur, and W. R. Mayr (eds.): Histocompatibility Testing 1984, pp. 58–63, Springer-Verlag, Berlin, 1984
Terasaki, P. L., Bernoco, D., Park, M. S., Ozturk, G., and Iwaki, Y.: Microdroplet testing for HLA-A, B, C and D antigens. Am. J. Clin. Pathol. 69: 103–120, 1978
Weitkamp, L. R., Bryson, M., and Bacon, G. E.: HLA and congenital adrenal hyperplasia linkage confirmed. Lancet 1: 931–932, 1978
White, P. C., New, M. I., and Dupont, B.: Cloning and expression of cDNA encoding a bovine adrenal cytochrome P-450 specific for steroid 21-hydroxylation. Proc. Natl. Acad. Sci. U.S.A. 81: 7505–7509, 1984
Whitehead, A. S., Woods, D. E., Fleischnick, E., Chin, J. E., Yunis, E. J., Katz, A. J., Gerald, P. S., Alper, C. A., and Colten, H. R.: DNA polymorphisms of the C4 genes: A new marker for analysis of the major histocompatibility complex. N. Engl. J. Med. 310: 88–94, 1984
Zappacosta, S., DeFelice, M., Monozzi, M., Lombardi, G., Valentino, R., and Vanacore, G.: HLA and congenital adrenal hyperplasia. Lancet 2: 524, 1978
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Layrisse, Z., White, C., Gunczler, P. et al. Sharing of MHC haplotypes among apparently unrelated patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Immunogenetics 25, 99–103 (1987). https://doi.org/10.1007/BF00364274
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF00364274