Laboratory of Immunogenetics and Tissue Immunology, Department of Clinical Immunology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland.
Department of Reproductive Medicine, Gameta Hospital, Rzgów, Poland.
Front Immunol. 2020 Jan 14;10:2982. doi: 10.3389/fimmu.2019.02982. eCollection 2019.
Infertility is currently a growing problem observed around the world and is estimated to affect between 8 and 12% of reproductive-aged couples worldwide. Artificial reproductive techniques are the last chance for couples seeking their own child. Human leukocyte antigen (HLA)-G expression has been suggested as an immunomodulatory molecule that influences pregnancy outcome. The gene encodes either membrane-bound or/and soluble proteins. The aim of this study was the evaluation of the role of soluble HLA-G (sHLA-G) and its gene polymorphism in successful implantation after fertilization embryo transfers (IVF-ETs) in different clinical protocols. We tested the polymorphism in three positions: rs1632947: c.-964G>A; rs1233334: c.-725G>C/T in promoter region; rs371194629: c.65_66insATTTGTTCATGCCT in 3' untranslated region of exon 8, in 389 patients who underwent IVF-ETs and 320 women with healthy children born after natural conception. Among the patient group, 239 women were with recurrent implantation failure and 117 women had an ongoing pregnancy or a child born after IVF-ET. We found that certain rs1632947-rs1233334-rs371194629 HLA-G haplotypes and diplotypes were associated with infertility, while others were protective. The lowest secretors of sHLA-G were G-C-ins haplotype carriers (37.21 IU/ml), while the highest -G-C-del carriers (73.80 IU/ml). Other haplotype carriers were intermediate secretors. In our study, regardless of possessed haplotype by the patient, 59.73 IU/ml sHLA-G was the threshold value with the best sensitivity (58.82%) and specificity (66.10%) to discriminate patients who achieved and maintained pregnancy from those who did not conceive or they had miscarriage ( = 0.0085; likelihood ratio, 1.74; 95% CI = 0.55-0.78). However, we do not exclude that factors other than sHLA-G may also contribute to complications in pregnancy. In addition, we found that IVF patients in cycles when frozen/thawed embryo was transferred secreted higher soluble HLA-G levels than patients with fresh embryo transferred ( = 0.021). Moreover, correlation analysis of sHLA-G concentration measured before and after embryo transfer for particular patients indicated short ovarian stimulation with gonadotropin-releasing hormone antagonist as more beneficial than long protocol with gonadotropin-releasing hormone agonist. Our study confirms a role of polymorphism in infertility and soluble HLA-G in the early stages of pregnancy.
不孕不育目前是全世界范围内一个日益严重的问题，据估计，全世界有 8%至 12%的育龄夫妇受到影响。人工生殖技术是寻求自身生育的夫妇的最后机会。人类白细胞抗原（HLA）-G 的表达被认为是一种免疫调节分子，影响妊娠结局。该基因编码膜结合或/和可溶性蛋白。本研究的目的是评估在不同临床方案中受精胚胎移植（IVF-ET）后可溶性 HLA-G（sHLA-G）及其基因多态性在成功植入中的作用。我们在三个位置测试了多态性：rs1632947：c.-964G>A；rs1233334：c.-725G>C/T 在启动子区域；rs371194629：c.65_66insATTTGTTCATGCCT 在 8 号外显子的 3'非翻译区，在 389 名接受 IVF-ET 的患者和 320 名自然受孕后生育健康儿童的女性中进行检测。在患者组中，239 名女性反复着床失败，117 名女性怀孕或 IVF-ET 后生育。我们发现，某些 rs1632947-rs1233334-rs371194629 HLA-G 单倍型和二倍型与不孕有关，而其他单倍型则具有保护作用。sHLA-G 分泌最低的是 G-C-ins 单倍型携带者（37.21IU/ml），而 G-C-del 携带者最高（73.80IU/ml）。其他单倍型携带者为中等分泌者。在我们的研究中，无论患者携带何种单倍型，59.73IU/ml 的 sHLA-G 是区分成功妊娠和维持妊娠与未妊娠或流产患者的最佳阈值（=0.0085；优势比，1.74；95%CI=0.55-0.78）。然而，我们不排除除 sHLA-G 以外的其他因素也可能导致妊娠并发症。此外，我们发现冷冻/解冻胚胎移植周期的 IVF 患者分泌的可溶性 HLA-G 水平高于新鲜胚胎移植患者（=0.021）。此外，对特定患者的胚胎移植前后 sHLA-G 浓度的相关分析表明，与促性腺激素释放激素激动剂长方案相比，促性腺激素释放激素拮抗剂短方案卵巢刺激更有益。我们的研究证实了 多态性在不孕不育中的作用和可溶性 HLA-G 在妊娠早期的作用。
