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Absence of close linkage between maternal genes for susceptibility to pre-eclampsia/eclampsia and HLA DR&bgr; To test the possibility that maternally expressed susceptibility genes for pre-eclampsia/eclampsia are closely linked to the HLA region on chromosome 6 of the human genome, members of ten pedigrees with multiple cases of these disorders were typed for HLA DR&bgr; restriction fragment length polymorphisms by means of Taql digests. The data were analysed by the LIPED program to calculate lod scores, by several programs to detect potential heterogeneity of recombination fraction between pedigrees, and by the affected-sibling and the affected-pedigree- member methods. The results exclude close linkage. If the putative susceptibility genes lie on chromosome 6 they must lie at least 5 centiMorgans, and probably more, from the HLA DR&bgr; loci. No indication of linkage at higher recombination fractions was found. The main maternally expressed genes affecting susceptibility to pre-eclampsia are not in the HLA region. Lancet 1990; 336: 653-57. Introduction Despite a century of investigation, the aetiology of pre- eclampsia and eclampsia remains unknown. Studies of the frequency of the disorder in blood relatives of index cases show that susceptibility is highly heritable.l-6 The power of conventional genetic analysis to reveal the exact mode of inheritance is limited by the facts that the phenotype is confmed to the one sex and that it occurs only in pregnancy, so it is possible that susceptibility is determined by the maternal genotype, by the fetal genotype, by an interaction between the two, or by some combination of these. Most of the simple pedigree data point to a major role for the maternal genotype,3-5 although some details are more easily interpreted in terms of an effect of the fetal genotype. 6,7 On the other hand, the various kinds of association between susceptibility and HLA types decisively implicate the fetal genotype. The reported differences from control groups include: greater homozygosity at the HLA B locus in women affected by pre-eclampsia and in their spouses;8 greater antigen sharing at the A and B loci9,10 and greater sharing of HLA DR47,11 between affected women and their spouses; association of HLA DR4 with risk of recurrence of non-proteinuric pregnancy hypertension," z increased heterozygosity at the B locus in eclamptic women," and a higher frequency of HLA B35 in babies born to eclamptic women. 14 Since the discoveries of an association between HLA and susceptibility to pre-eclampsia,8,9 the possibility that there are susceptibility genes linked to the HLA locus has been raised several times.7.11,12,15 Kilpatrick and colleagues,7 have lately proposed a very specific hypothesis-that pre- eclampsia occurs when both mother and fetus are homozygous for the one HLA-linked recessive gene. We have examined this hypothesis by testing for linkage between maternally expressed genes for susceptibility and HLA DR&bgr;. Patients and methods Ten multi-case pedigrees were ascertained, each through a single index case, by interviewing patients who presented at the Monash ADDRESSES: School of Biological Sciences, Macquarie University, New South Wales (A. N. Wilton, PhD, Prof D. W. Cooper, PhD, P. Marshall, BSc) and Monash Perinatal Unit, Department of Obstetrics and Gynaecology, Monash University, Victoria, Australia (S. P. Brennecke, FRACOG, S, M. Bishop, RN). Correspondence to Prof D. W. Cooper, School of Biological Sciences, Macquarie University, NSW 2109, Australia.