HLA-DR and - DQ (2000 patients) in RPL in the Danish Population

Background: In previous smaller studies we found that the HLA-DR3-DQ2 haplotype is more frequent in Caucasian women with unexplained recurrent pregnancy loss (RPL). This haplotype is associated with several autoimmune diseases.

Objectives: Using up-to-date technology for DNA-based HLA determination we wanted to confirm or reject our previous findings regarding the role of HLA-DR3-DQ2 in RPL in the so far largest case-control study and to investigate whether other HLA-DR/DQ alleles are associated with RPL.

Methods: HLA-DRB1 typing and in subsets of patients also HLA-DQB1 typing were done in 1079 Caucasian women with unexplained RPL (defined as 3 or more consecutive early pregnancy losses) and 230 control women with a least one normal birth and maximum one pregnancy loss. The patients have been included between January 2003 and May 2016. Patients with uterine abnormalities, parental chromosomal aberrations or oligomenorrhea were excluded.

Results: The HLA-DRB1*03-DQB1*02 haplotype was found in 24.5% of all RPL patients, 26.6% of patients with 4 or more pregnancy losses and 18.7% of controls (p = 0.06 and p < 0.02 respectively). The HLA-DRB1*07 allele was found in 21.9% of RPL patients and in 16.1% of controls (p < 0.05). In Caucasians, most HLA-DRB1*07 alleles are found in the HLA-DR7-DQB1*02 haplotype and in order to investigate whether the DQB1*02 alleles is the common susceptibility allele for RPL, investigation of HLA-DQB1 polymorphisms was undertaken in HLA-DRB1*07 positive patients and controls. This did not reveal any significant difference between patients and controls. The frequency of the HLA-DRB1*04 allele among patients was 31.0% vs. 38.7% among controls (P< 0.025). When comparing the frequency of HLA-DRB1*04 homozygous patients and controls, the difference became even more significant (P < 0.001). Results will be presented whether specific HLA-DRB1*04 subtypes or different HLA-DQB1 types linked with HLA-DRB1*04 are the main polymorphisms conferring RPL protection. The frequencies of none of the other HLA-DRB1 alleles were different between the two groups. There was no clear correlation between primary/secondary RPL status or number of pregnancy losses and presence of specific HLA alleles except for HLA-DRB1*03, which were more frequent in patients with ≥4 pregnancy losses.

Conclusions: The association between HLA-DRB1*03 and RPL from our previous studies was confirmed, although the association was weaker. This study revealed that HLA-DRB1*07 seems to predispose and HLA-DRB1*04 seems to be protective against RPL, which both are new findings. The results suggest that immune reactions dependent of antigen presentation by class II HLA molecules are important in RPL classified as unexplained after conventional screening.