The HLA‐G 14 bp insertion/deletion polymorphism and its association with soluble HLA‐G levels in women with recurrent miscarriages

Abstract

HLA-G, a nonclassical class-Ib gene is mainly expressed on extravillous trophoblasts at the fetal-maternal interface. HLA-G molecule is considered to play an important role in maternal immune suppression during pregnancy. The 14 bp insertion/deletion polymorphism (rs66554220) in exon eight of the HLA-G gene influences HLA-G mRNA stability and isoform splicing patterns. In this study, 202 recurrent miscarriage (RM) women with two or more than two consecutive miscarriages, their 202 partners and 204 fertile control women with at least one live birth and no miscarriages were analyzed for 14 bp insertion/deletion polymorphism. Soluble HLA-G (sHLA-G) levels were also determined and compared between randomly selected 111 RM women and 111 control women using QAYEE-Bio ELISA kits. Student's t test and χ test were used to depict the statistical differences. The results showed no significant differences for 14 bp allele and genotype frequencies between the study groups. However, our study showed a significant difference (P = .0107) for sHLA-G levels in RM women and control women. Furthermore, a significant difference (P = .0135) for sHLA-G levels in relation to +/-14 bp heterozygous genotype was seen between the two groups. The 14 bp allele sharing between the partners did not show any significant association with the number of miscarriages in RM couples. The association of 14 bp polymorphism and recurrent miscarriages was not significant in our study.

Increased HLA-G Expression in Term Placenta of Women with a History of Recurrent Miscarriage Despite Their Genetic Predisposition to Decreased HLA-G Levels

“…Remarkably, the present immune-histochemical analysis of term placentas of successful pregnancies showed a significantly higher HLA-G protein expression in women with a history of RM compared to controls, although this RM group had a lower frequency of the 14 bp del/del genotype. This is not in line with results previously found in peripheral blood [21,33] and suggests that local regulation is involved. HLA-G was mostly confined to the trophoblast areas at the fetal-maternal interface (decidua basalis), as determined by double label immunofluorescence experiments (Figure S2), and the level of HLA-G expression was independent of previous pregnancies.…”

“…However, we found a higher frequency of HLA-G 14-bp ins/del heterozygotes in RM women (65.2%) as compared with control women (39.1%), and a lower frequency of HLA-G 14 bp del/del homozygotes (17.4% and 43.2%, respectively). This is consistent with some studies [21,22,23], but not others [24,25]. Since several studies have focused on the HLA-G 14-bp polymorphism in RM with controversial or inconclusive results, Wang et al performed a meta-analysis [26], which suggested that the HLA-G 14-bp insertion allele was associated with an increased risk of RM.…”

HLA-G Genotype/Expression/Disease Association Studies: Success, Hurdles, and Perspectives

“…However, several indirect evidences prompted investigators to correlate the presence of specific miRNA with HLA-G protein expression in vivo. In placenta, miR-148a and miR-152 are poorly expressed, whereas the HLA-G mRNA levels are high (58). Since miR-148a and miR-152 down-regulate HLA-G1 protein expression in cell lines, a possible inverse relationship between these molecules in placenta has been postulated (58).…”

“…In placenta, miR-148a and miR-152 are poorly expressed, whereas the HLA-G mRNA levels are high (58). Since miR-148a and miR-152 down-regulate HLA-G1 protein expression in cell lines, a possible inverse relationship between these molecules in placenta has been postulated (58). Similarly, miR-133 reduced HLA-G protein expression in trophoblast cell lines (59), and its low expression in primary colorectal cancer samples, in which the HLA-G levels are high (60), suggested a possible inverse correlation of these molecules.…”

Soluble HLA-G Expression Inversely Correlates With Fetal Microchimerism Levels in Peripheral Blood From Women With Scleroderma

“…Nevertheless, maternal monocytes and dendritic cells express membrane-bound and soluble HLA-G (sHLA-G), respectively ( 19 ). The role of maternal HLA-G on the immune tolerance process in pregnancy is poorly understood, although data show that maternal HLA-G polymorphisms as well as maternal sHLA-G expression could influence pregnancy outcome ( 20 , 21 ).…”