Tissue Antigens (1978), 1 2 , 398-401

SHORT COMMUNICATION

Published by Munksgaard, Copenhagen, Denmark No part may be reproduced by any process without written permission from the author (s)

HLA Antigens in Patients with Idiopathic

Hemochromatosis (IH) P. Kiihnl, J.P. Kaltwasser and S. Seidl Institute of Immunohematology, and Department of Hematology, Center of Internal Medicine University of FrankfurdMain, Federal Republic of Germany Received for publication 3 July, revised, accepted 24 July 1978

Several different haplotypes appear to be associated with idiopathic hemochromatosis (IH); one French group (Simon e t al. 1976) observed a striking increase of the alleles A3 and B14 in a series of 51 patients, A3 being 7 8 . 4 % ~ . 27.0%, and B14 being 2 5 . 5 % ~ ~3.4% . in a control group. This assumed linkage of histocompatibility genes to genes responsible for the disease was also noted in England by Bomford et al. (1977) who observed a significant increase of A3 in 3 5 patients with IH ( 6 9 % ~ ~31%), . suggesting that the full development of the disease possibly depends on the concomitant inheritance of two different disease susceptibility genes (= separate metabolic defects): one linked to A3/B14/Cw5 (increased plasma to storage iron exchange) and the other to A1 1/B27/Cw2 (increased iron absorption). Contradictory reports came from three small series investigated in Ireland, Scotland and South-Western Germany (Walters e t al. 1975, Shewan et al. 1976. Henke & Ungar 1978). In these studies a significant excess of the A3lB7 haplotype

was found. The purpose of the present work was to study the correlation between HLA types and IH in patients from Germany and t o further settle the issue of the two deviating haplotype associations in question. Material a n d Methods

Thirty-five unrelated patients with overt well-documented IH were typed (31 male and four female). Skin pigmentation, hepatomegaly, diabetes mellitus, heart failure, elevated serum iron (> 200 y %) unsaturated iron binding capacity < SO%, an increased intestinal 59 Fe absorption rate and positive liver biopsy were typical signs and symptoms in patients with IH. The control group used for comparison comprised 100 presumably healthy blood donors from Hessen. Tissue typing of almost all known A, B, and C antigens was performed, using the NIH standard microlymphocytotoxicity assay. Besides HLA typing, Bf (properdin factor B) was determined according to Mauff et al. (1975) because of a known

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significant three-point association of the haplotype A3, B7, Bfs; since a similar disequilibrium exists with Dw2, typing for this antigen was also performed (Albert et al. 1977). The frequencies of A3 (74.3 vs. 21.0%; x2 (Yates’) = 30.13; P < O . O 0 0 5 ; RR = 10.8) and of B7 ( 6 0 . 0 ~ s2. 2 . 0 % ; ~ ’= 15.54; P < 0.0005;RR = 5.3) were significantly elevated in our patients compared with healthy controls. The increase in the frequency of B7 was statistically less significant than the prevalence of A3. This is probably caused by the known high linkage disequilibrium between these two antigens. The allelic association of A3 and B7 was likewise more frequent in the IH patients than in controls ( 5 4 . 3 % ~8.0%). ~. In 1 4 of 26 A3-positive patients, vs. four of 21 A3positive controls, the pattern A3-blank indicated a higher degree of possible homozygosity. This difference is significant ( P < 0.015), indicating that a dose effect may be involved, as discussed previously (Simon e t al. 1977b). HLA-D typing could be performed in 1 3 patients. Five of them were Dw2 positive, four of whom had A3lB7, indicating no strong association so far. The frequency of BfF was lowered to 0.08 in 1 3 patients compared with 0.1798 in a random sample from Hessen (n = 542; Kuhnl & Spielmann, 1978) although this correlation was not yet significant. The observed RR-value of 10.8 for A3 is in good accord with the data obtained by Simon e t al. (1976) who found an RR-value of 9.9 and with other groups, although our RR-value seems to be the highest hitherto described. The RR of 5.3 for B7, on the other hand, is also statistically significant and confirms the results of the groups in Ireland, Scotland and South-Western Germany. Only one of our 35 unrelated patients was positive for

B14, in South-Western Germany none of 11 unrelated IH patients was B14 positive. These findings are clearly in contrast to those reported from France and England, which were confirmed by family studies (Simon e t al. 1977a). We may therefore discuss the two different haplotype associations in terms of one or a few DS-genes located near the A locus which were separated by an intra-HLA crossover in a common ancestor from the “original” A3lB7 haplotype and inherited together with A3/B14 in the offspring. In view of the RR-values, HLA typing might be of some importance t o relatives of IH patients in order to detect persons a t high risk and to start early therapy. In unrelated individuals, screening for A3 lB7 is of minor value, because the frequency of A3/B7 is too high in the Caucasoid population.

References Albert, E.D., Rittner, C., Scholz, S. Kuntz, B. & Mickey, M.R. (1977) Three-Point Association of HLA-A, B, Bf Haplotypes Deduced in 200 Parents of 100 Families. Scand, J. Immunol. 6 , 4 59-464. Bomford, A., Eddleston, A.L.W.F., Kennedy, L.A., Batchelor, J.R. & Williams, R. (1977) Histocompatibility antigens as markers of abnormal iron metabolism in patients with idiopathic haemochromatosis and their relatives. Lancet 1, 327-329. Henke, J. & Ungar, W. (1978) HLA-Antigens in Idiopathic Haemochromatosis (i.h.) Preliminary report. 2. Immun. -Forscb. 154,41-43. Kuhnl, P. & Spielmann, W. (1978) Properdin Factor B-Polymorphism in the Population of Hessen, Germany. Z. Recbtsmedizin 81, 125-131. Mauff, G . , Hummel, K. & Pulverer, G. (1975) Properdin Factor B (Glycine-rich betaGlycoprotein or C3 Proactivator)-Polymorphism: Genetic and Biochemical AspectsFirst Application to Paternity Cases. 2. Zmmun. -Forscb. 150, 327-338.

HLA ANTIGENS IN IH Shewan, W.G., Mouat, S.A. & Allan, T.M. (1976) HLA antigens in haemochromatosis. Brit. wed. J . 1 , 281-282. Simon, M., Alexandre, J.-L., Bourel, M., LeMarec, B. & Scordia, C. (1977b) Heredity of idiopathic haemochromatosis: A study of 106 families. Clin. Genet. 11, 327-341. Simon, M., Bourel, M., Fauchet, R. & Genetet, B. (1976) Association of HLA-A3 and HLAB14 antigens with idiopathic haemochromatosis. Gut. 1 7 , 332-334. Simon, M., Bourel, M., Genetet, B. & Fauchet, R. (1977a) Idiopathic hemochromatosis. Demon-

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stration of recessive transmission and early detection by family HLA typing. New Engl. J . Med. 297,1017-1021. Walters, J. M., Watt, D.W., Stevens, F.M. & McCarthy, C.F. (1975) HLA antigens in haemochromatosis. Brit. med. J. 4 ( 5 5 9 9 , 520. Address: Dr. P. Kiihnl Institut fur Immunhamatologie der Universitat Sandhofstrde 1 D-6000 FrankfurdMain Federal Republic Germany

HLA antigens in patients with idiopathic hemochromatosis (IH).

Tissue Antigens (1978), 1 2 , 398-401 SHORT COMMUNICATION Published by Munksgaard, Copenhagen, Denmark No part may be reproduced by any process with...
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