Human leukocyte antigen (HLA)-G is an immune modulating molecule that is present on fetal extravillous trophoblasts at the fetal-maternal interface. Single nucleotide polymorphisms (SNPs) in the 3 prime untranslated region (3′UTR) of the HLA-G gene can affect the level of HLA-G expression, which may be altered in women with recurrent miscarriages (RM). This case-control study included 23 women with a medical history of three or more consecutive miscarriages who delivered a child after uncomplicated pregnancy, and 46 controls with uncomplicated pregnancy. Genomic DNA was isolated to sequence the 3′UTR of HLA-G. Tissue from term placentas was processed to quantify the HLA-G protein and mRNA levels. The women with a history of RM had a lower frequency of the HLA-G 3′UTR 14-bp del/del genotype as compared to controls (Odds ratio (OR) 0.28; p = 0.039), which has previously been related to higher soluble HLA-G levels. Yet, HLA-G protein (OR 6.67; p = 0.006) and mRNA (OR 6.33; p = 0.010) expression was increased in term placentas of women with a history of RM as compared to controls. In conclusion, during a successful pregnancy, HLA-G expression is elevated in term placentas from women with a history of RM as compared to controls, despite a genetic predisposition that is associated with decreased HLA-G levels. These findings suggest that HLA-G upregulation could be a compensatory mechanism in the occurrence of RM to achieve an ongoing pregnancy.

Soluble HLA‐G (sHLA‐G) levels in human seminal plasma (SP) can be diverse and may affect the establishment of maternal‐fetal tolerance and thereby the outcome of pregnancy. We investigated whether sHLA‐G levels in SP are associated with polymorphisms in the 3′‐untranslated region (UTR) and UTR haplotypes of the HLA‐G gene. Furthermore, we compared the HLA‐G genotype distribution and sHLA‐G levels between men, whose partner experienced unexplained recurrent miscarriage (RM), and controls. Soluble HLA‐G levels (n = 156) and HLA‐G genotyping (n = 176) were determined in SP samples. The concentration of sHLA‐G was significantly associated with several single‐nucleotide polymorphisms (SNPs): the 14 base pair (bp) insertion/deletion (indel), +3010, +3142, +3187, +3196, and + 3509. High levels of sHLA‐G were associated with UTR‐1 and low levels with UTR‐2, UTR‐4, and UTR‐7 (P < .0001). HLA‐G genotype distribution and sHLA‐G levels in SP were not significantly different between the RM group (n = 44) and controls (n = 31). In conclusion, seminal sHLA‐G levels are associated with both singular SNPs and 3UTR haplotypes. HLA‐G genotype and sHLA‐G levels in SP are not different between men whose partner experienced RM and controls, indicating that miscarriages are not solely the result of low sHLA‐G levels in SP. Instead, it is more likely that these miscarriages are the result of a multifactorial immunologic mechanism, whereby the HLA‐G 3′UTR 14 bp ins/ins genotype plays a role in a proportion of the cases. Future studies should look into the functions of sHLA‐G in SP and the consequences of low or high levels on the chance to conceive.