Soluble HLA-G levels in seminal plasma are associated with HLA-G 3'UTR genotypes and haplotypes

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.