A CANDIDATE GENETIC MARKER FOR REPRODUCTIVE FAILURE.
M.Tevfik Dorak, HKG Machulla, T Lawson, C Darke, KI Mills, AK Burnett.  Dept of Haematology, University of Wales College of Medicine, Cardiff, U.K.


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Parental HLA-DR allelic sharing is increased in both leukemia and pregnancy failure which suggests either lack of feto-maternal disparity or HLA-DR-linked recessive lethal genes have deleterious effects in pregnancy. We previously postulated the recessive nature of the MHC association with leukemia and a common immunogenetic basis for leukaemia and spontaneous abortions (Dorak & Burnett, Cancer Causes & Control 1992;3:273). We have now examined the immunogenetics of childhood acute lymphoblastic leukemia (ALL) in 109 patients and 309 local newborns by the Biotest DRB-ELPHA typing system. Homozygosity for HLA-DRB4*01 (-DR53) showed a very strong association with common ALL only in boys (34.2% vs 3.6% in controls; p<0.00001; OR=13.9, 95% CI=5.2-37.4). The leukemia susceptibility genotype had a deficit in newborn boys (n=139, 3.6% vs expected 8.7%; p=0.03). Girls (n=170) showed no deficit (10.6% vs 8.7%). The deficit in boys was also significant against the female-specific rate (p=0.03) and the frequency in healthy adults (13.3%; p=0.001). These results agree with the increased frequency of spontaneous abortions in the maternal history of children with ALL, the increased risk of leukemia in survivors of threatened abortions, and the consistent association of HLA-DR53 with the commonest known cause of recurrent spontaneous abortions (anti-phospholipid antibody syndrome). We now show that homozygosity for HLA-DRB4*01 (-DR53) is not only involved in leukemia susceptibility but also in reproductive failure with male-specificity.