HLA CLASS-II ALLELES CONFER SUSCEPTIBILITY TO RECURRENT FETAL LOSSES IN DANISH WOMEN

HLA-DR and -DQ typings were performed by a combination of RFLP and PCR-SSP techniques in 234 Danish women with at least three consecutive unexplained fetal losses (recurrent fetal losses) and 360 controls and the DRB1, DQA1 and DQB1 alleles were deduced. In the total group of patients, the frequency of no DRB1-DQA1-DQB1 haplotype was significantly increased compared with controls. In the subgroup of 97 women with four or more fetal losses (multiple fetal loss group), the frequency of women carrying the DRB1*0101, DQA1*0101, DQB1*0501; DRB1*0102, DQA1*0101, DQB1*0501 and DRB1*0103, DQA1*0101, DQB1*0501 haplotypes or the DRB1*0301, DQA1*0501, DQB1*0201 haplotype were significantly increased compared with controls (RR=2.1; p(c)<0.05 with regard to former three haplotypes combined and RR=2.2; p(c)<0.05 for the latter). The frequency of women with at least one of the four haplotypes was significantly (p<0.002) increased with the number of previous fetal losses in the women's history. Analysis of the DQA1 and DQB1 phenotypes in women with at least four fetal losses showed that DQA1*0501 and DQB1*0501 were increased compared with controls (RR=1.9; p(c)<0.05 and RR=2.2; p(c)<0.025, respectively). Analysis of DRB1-DQA1-DQB1/DRB1-DQA1-DQB1 genotypes suggested that genotypes comprising both DQA1*0501 and DQB1*0501 alleles (in trans) exhibited a higher RR for experiencing at least four fetal losses (RR=3.4, p=0.002) than each of the alleles did alone. Genotypes comprising a DQB1 allele encoding a beta chain negative for aspartate in position 57 were associated with an increased RR (2.3; p<0.01) for multiple fetal losses and the etiologic fraction was high (0.49). The results suggest that genes or gene-sequences, linked to the DRB1*0101, DQA1*0101, DQB1*0501; DRB1*0102, DQA1*0101, DQB1*0501; DRB1*0103, DQA1*0101, DQB1*0501 and DRB1*0301, DQA1*0501, DQB1*0201 haplotypes, confer susceptibility to multiple fetal losses. These alleles/gene-sequences are presumably located in the DQA1 and DQB1 loci and may elicit their effect by mediating an autoimmune reaction against one or more trophoblast antigens.