lmmunogenetics38: 421-429, 1993 _//H/H/HlO- genetics © Springer-Verlag 1993 Polymorphism of the DQA1 promoter region (QAP) and DRB1, QAP,DQA1, DQB1 haplotypes in systemic lupus erythematosus Zhu Yao 1, Akinori Kimura 2, Klaus Hartung3, Peter J. Haas1, Andrea Volggerl, Giinter Briinnlerl, Jiirgen B6nisch 1, Ekkehard D. Albert 1, SLE study group members* 1ImmungeneticsLaboratory,Kinderpoliklinik, Universityof Munich, Pettenkoferstrasse 8 a, 80336 Munich, Germany 2Departmentof Genetics,Medical Institute of Bioregulation,KyushuUniversity,3-1-1 Maidashi, Higashi-ku,Fukuoka 812, Japan 3Private Institute of Immunologyand MolecularGenetics, Kriegsstrasse99, 76133 Karlsruhe,Germany ReceivedMay 18, 1993/Revised versionreceivedJune 21, 1993 Abstract. We have investigated the DNA polymor- phism for the DQA1 promoter region (QAP) and HLA- class II DRB1, DQA1, and DQB1 genes in 178 central European patients with Systemic lupus erythematosus (SLE) using polymerase chain reaction and Dig-ddUTP labeled oligonucleotides. Increased frequencies of DRBl*02 and *03 are confirmed by DNA typing. In addition, the frequencies of DQAI*0501, "0102 and DQB1 "0201, *0602 alleles are increased in the patients as compared to controls. The strongest association to SLE is found with DRB1 *03 and DQB1 "0201 alleles (p <10 -7, p corr. <10 -5 and p <10 -6, p corr. <10 -4, respectively). By investigating the DQA1 promoter re- gion in the SLE patients we have detected nine different QAP variants. Increased frequencies of QAP1.2 and QAP4.1 are observed in patients as compared to con- trols (p <0.05, p corr. = n.s.). Analysis of linkage dis- equilibria demonstrates a very strong association be- tween QAP variants and DQA1, DRB1 alleles. Certain QAP variants are completely associated with DQA1 and DRB1 alleles, whereas others can combine with different DQA1 and DRB1 alleles. All DRB1 *02-posi- tive patients and controls carry QAP1.2, and all DRB1 *03-positive patients and controls carry QAP4.1. Conversely, the QAP1.2 variant appears only in DRB1 *02 haplotypes, while the QAP4.1 variant can be observed in DRBI*03, *11, and "1303 haplotypes. Based on the strong linkage disequilibria between DRB1-DQA1-DQB1 genes and between DRB1-QAP- DQA1, we have deduced the four-point haplotypes for DRB1-QAP-DQA1-DQB1 in patients and controls. * SLE study group members: M. Baur, A. Corvetta, H. Ehrfeld, J. Frey, J. R. Kalden, E Krapf, B. Lang, G. G. Lange, K. Pirner, C. Rittner, E. Rtther, R Schneider,H. E Seelig, S. Seuchter,W. Stan- gel, C. Specker,R Sp~ith,H. Deicher. Correspondence to: Z. Yao. Two haplotypes DRBl*O2-QAP1.2-DQAl*0102- DQBl*0602 and DRBI*O3-QAP4.1-DQA1 *0501- DQBl*0201 are significantly increased in patients as compared to controls (p <0.01, p corr. = n. s., RR = 1.8 andp <10-7,p corr. <10 -5, RR = 3.1, respectively). The analysis of relative risks attributed to the various alleles of QAP, DQA1, and DQB1 as well as the investigation of the deduced DRB1-QAP-DQA1-DQB1 haplotypes leads to the conclusion that QAP4.1 and DQA1 "0501 on the DR3 haplotypes are probably not involved in SLE susceptibility. There is no evidence for the in- volvement of DQ2 ot/~ dimers coded in transposition. Thus, susceptibility to SLE is on the DR3 haplotype most probably localized at DRB1 or telomeric of DRB1, while for the DR2 haplotype such orientation cannot be given. Introduction Several lines of evidence indicate that genetic factors are critical in the development of systemic lupus erythematosus (SLE; Arnett et al. 1976; Block et al. 1975, 1976; Ballou et al. 1982). In order to detect the genetic predisposition in patients with SLE, the poly- morphic genes within the major histocompatibility complex have been studied (Grumet et al. 1971; Goldberg et al. 1976). Various HLA antigens have been found to be associated with SLE; however, the strengths and specificities of the associations vary in studies and in ethnically different populations (Reinert- sen et al. 1978; Howard et al. 1986; Hawkins et al. 1987; Reveille et al. 1989; Schur et al. 1990; Gomez- Reino et al. 1991; Doherty et al. 1992). In a large number of patients from a central European multicenter study for SLE, increased frequencies of HLA-B 8, -DR3