HLA-G 14 bp Polymorphism and Risk of Pre-Eclampsia

Research Article

Austin Hypertens. 2016; 1(2): 1006.

HLA-G 14 bp Polymorphism and Risk of Pre-Eclampsia

Durmanova V¹ and Drobny J²*

¹Institute of Immunology, Faculty of Medicine, Comenius University in Bratislava, Slovakia

²Department of Obstetrics and Gynecology, Faculty of Medicine, Comenius University in Bratislava, Slovakia

*Corresponding author: Drobny J, Department of Obstetrics and Gynecology, Comenius University in Bratislava, Slovakia

Received: July 29, 2016; Accepted: August 29, 2016; Published: September 09, 2016


Objective: Pre-Eclampsia (PE) is a serious pregnancy-specific disease but its cause remains to be unknown. Although PE is characterized mainly by hypertension and proteinuria, variety of clinical signs and symptoms showed multi organ damage in women with PE. Study of altered maternal immunoadaptation to pregnancy seems to be the key element in creation of new clinical predictive markers of PE. Human Leukocyte Antigen G (HLA-G) belongs to non-classical HLA class I protein with various immunosuppressive functions. The main biological function of HLA-G is to induce fetal tolerance against maternal immune system. As gene polymorphism can decrease protein expression level, we studied an impact of HLA-G 14 bp insertion/deletion polymorphism on risk for PE.

Methods: 102 women suffering from PE and 121 women with physiological pregnancies were enrolled in the study. To analyze the presence of 14 bp insert in the HLA-G exon 8, PCR was performed.

Results: We found no statistically significant differences of HLA-G 14 bp deletion/insertion allele and genotypes between women with PE and control group. Nevertheless in the women with PE we observed higher frequencies of the homozygous +14/+14 bp genotype in comparison to control group (23.53% vs. 19.01%, P = 0.4095).

Conclusion: Our results have shown a tendency of association between HLA-G 14 bp insertion polymorphism and risk for PE. Further investigation is needed to determine the role of HLA-G 14 bp polymorphism in PE development. Moreover, translational research of PE is unavoidable, too.

Keywords: HLA-G; Pre-eclampsia; 14 bp Polymorphism; Genotyping


HLA-G: Human Leukocyte Antigen G; PE: Pre-Eclampsia; IUGR: Intrauterine Growth Restriction; HELLP: Hemolytic Elevated Liver Enzymes and Low Platelets; TGF: Transforming Growth Factor; ILT: Immunoglobulin-Like Transcript Receptor; APC: Antigen- Presenting Cell; KIR: Killer-Immunoglobulin Like Receptors; NK: Natural Killer; CD: Cluster of Designation; UTR: Untranslated Region; BP: Base Pair; Snp: Single Nucleotide Polymorphism; PCR: Polymerase Chain Reaction; OR: Odds Ratio; 95%CI: Confidence Interval; Ins: Insertion; Del: Deletion; CVD: Cardiovascular Disease


Pre-eclampsia belongs to one of very serious complication during pregnancy. It is a multisystem disorder that is manifested by hypertension, proteinuria and abnormal blood clotting. Advanced clinical symptoms include seizures, renal failure, IUGR (Intrauterine Growth Restriction) and/or HELLP (Hemolysis, Elevated Liver Enzymes and Low Platelets) syndrome. Finally the generalized damage of the maternal endothelium, kidneys and liver can develop leading to increased mortality of mother as well as foetus. The clinical symptoms of pre-eclampsia can be observed in the second or the third trimester in pregnancy and are the most common in primiparas [1]. Clinical features of PE are studied by Doppler flowmetry not only in foetal [2] and foetoplacental circulation [3], as well as in maternal organs, i.e. uterine [4], cerebral [5], ophtalmic [6] and renal vessels [7]. Stiffness [8], metabolic syndrome [9,10] and risk of CVD [11] are other clinical research topics.

Despite many research studies, the pathology of pre-eclampsia is not fully understood. One cause may originate in an insufficiently developed placenta, referred to as poor placentation. It is characterized by impaired remodeling of spiral arteries of the uterus (endothelial dysfunction) caused by an imbalance of circulating angiogenic factors. High circulating levels of soluble Fms like tyrosine kinase 1 (sFlt1) and soluble endoglin (sEng), a circulating receptor or TGFbeta, (both anti-angiogenic factors) and low levels of circulating Vascular Endothelial Growth Factor (VEGF) and Placental Growth Factor (PlGF) (both pro-angiogenic factors) have been described [12].

There are also immunological factors that can induce pregnancy disorders including pre-eclampsia. One of the immune molecules that play a beneficial role in the pregnancy is the Human Leukocyte Antigen G (HLA-G). HLA-G is a non-classical HLA class I protein that exerts various immunosuppressive functions. The molecule is mainly expressed on trophoblast cells in the foetal placenta and induces the immune tolerance of foetus [13]. Immunosuppressive activity of HLA-G molecule is mediated through its interaction with inhibitory receptors of immune cells: ILT-2 present on B, APC and some T, NK cells, ILT-4 on APC and KIR2DL4 expressed by NK and some T cells [14,15]. Thus HLA-G mediates inhibition of cytotoxic activity of uterine and peripheral blood NK cells and CD8+ T cells, inhibition of all proliferative response of CD4+ T cells; inhibition of Dendritic cells maturation and activates regulatory T cells [15].

The HLA-G gene is 4170 bp long and consists of 8 exons. By an alternative splicing of the primary transcript, 7 HLA-G isoforms can be generated. Four isoforms HLA-G1, -G2, -G3 and -G4 are membrane bound, whereas three isoforms HLA-G5, -G6 and -G7 are soluble. Only the structure of HLA-G1 molecule resembles to the structure of other membrane-bound HLA-I molecules [16].

HLA-G gene is characterized by low polymorphism, namely 53 HLA-G alleles, 18 HLA-G proteins and 2 null alleles have been identified until now (IMGT/HLA database, April 2016). The most polymorphic sites that influence HLA-G expression were identified in the 5′ and 3′ non-coding regions. In the 3′ UTR the 14 bp insertion polymorphism (5′-ATTTGTTCATGCCT-3′) was described, that affects stability of mRNA causing lower production of most membrane and soluble isoforms [17]. Other polymorphisms in the 3′ UTR that can influence mRNA stability and sHLA-G level includes SNP at the +3142 position (C/G), at the +3187 (A/G) and +3196 (C/G) [18].

The important role of HLA-G in pre-eclampsia was determined through observations of decreased HLA-G levels in the maternal serum [19-21]. As the expression of sHLA-G may be influenced by the 14 bp insertion polymorphism [17], the possible association between this variant and risk for PE was investigated, but the results are controversial. Some studies found a significant increase of +14/+14 genotype in women with PE in comparison to women with physiological pregnancies [22,23]. Other studies didn’t reveal such SNP association with PE development [24-26]. In our study we followed the association of HLA-G 14 bp insertion/deletion polymorphism on risk for PE in Slovak Caucasoid population.


Study subjects

The investigated group included 102 women suffering from pre-eclampsia and 121 women with physiological pregnancies. PE was defined as blood pressure of at least 140/90 mmHg with readings at least 6 h apart and proteinuria (300 mg/24 h or ≥30 mg/ dl by urine analysis [27]. The clinical characteristics of the women with PE are shown in Table 1. All study subjects provided written informed consent for enrolling in the study and for personal data management. The study was approved by the Ethics committee of the University Hospital Bratislava. All the investigations were carried out in accordance with the International Ethical Guidelines and the Declaration of Helsinki.