The Association of HLA-G Gene Polymorphism and Its Soluble Form With Male Infertility.

Karolina Piekarska,Izabela Nowak,Michał Radwan,Agnieszka Tarnowska,Paweł Radwan,Jacek R Wilczyński,Andrzej Wiśniewski,Andrzej Malinowski,Rafał Krasiński

doi:10.3389/fimmu.2021.791399

Abstract

Successful reproduction depends on many factors. Male factors contribute to infertility in approximately 50% of couples who fail to conceive. Seminal plasma consists of secretions from different accessory glands containing a mixture of various cytokines, chemokines, and growth factors, which together can induce a local immune response that might impact on a male’s as well as a female’s fertility. Human leukocyte antigen (HLA)-G expression has been suggested as an immunomodulatory molecule that influences pregnancy outcome. The HLA-G gene encodes either membrane-bound or/and soluble proteins. The aim of this study was the evaluation of HLA-G polymorphisms and their impact on soluble HLA-G (sHLA-G) production. We tested the HLA-G polymorphism in three positions: rs1632947: c.-964G>A; rs1233334: c.-725G>C/T in the promoter region; rs371194629: c.∗65_∗66insATTTGTTCATGCCT in the 3′ untranslated region. We tested two cohorts of men: 663 who participated in in vitro fertilization (test material was blood or sperm), and 320 fertile controls who possessed children born after natural conception (test material was blood). Since 50% of men visiting assisted reproductive clinics have abnormal semen parameters, we wondered if men with normal sperm parameters differ from those with abnormal parameters in terms of HLA-G polymorphism and secretion of sHLA-G into semen. We found that certain rs1632947-rs1233334-rs371194629 HLA-G haplotypes and diplotypes were associated with male infertility, while others were protective. Normozoospermic men with the A-C-del haplotype and A-C-del/A-C-del diplotype secreted the most sHLA-G into semen (574.1 IU/mL and 1047.0 IU/mL, respectively), while those with the G-C-ins haplotype and G-C-ins/G-C-ins diplotype – the least (80.8 IU/mL and 75.7 IU/mL, respectively). Men with the remaining haplotypes/diplotypes secreted sHLA-G at an intermediate level. However, only in one haplotype, namely G-C-ins, did we observe strong significant differences in the concentration of sHLA-G in the semen of men with teratozoospermia compared to men with normal sperm parameters (p = 0.009). In conclusion, fertile men differ in the profile of HLA-G polymorphism from men participating in IVF. Among all HLA-G haplotypes, the most unfavorable for male fertility is the G-C-ins haplotype, which determines the secretion of the lowest concentration of the soluble HLA-G molecule. This haplotype may reduce sperm parameters.

Highlights

HLA-G Polymorphism in Fertile Men and Men Participating in in vitro fertilization (IVF)
Out of 9 detected haplotypes, 2 of them (A-C-ins and G-G-del) were statistically significantly more frequent in the group of fertile men compared to men participating in in vitro fertilization (p < 0.0001/pcorr. = 0.0004, odds ratio (OR) = 0.653, 95% CI = 0.53-0.80; p = 0.005/ pcorr. = 0.042, OR = 0.648, 95% CI = 0.48-0.88, respectively, Table 1)
Diplotypes A-C-del/A-G-del and G-C-ins/G-C-ins were more prevalent in patients than controls (p = 0.0001/ pcorr. = 0.002, OR = 4.857, 95% CI = 1.91-15.81; p < 0.0001/ pcorr. = 0.001, OR = 3.066, 95% CI = 1.72-5.82, respectively, Table 2)

Summary

Introduction

Male factors contribute to infertility in approximately 50% of couples who fail to conceive [1]. This is a growing problem observed around the world and in Poland [2]. Decreased semen quality has been observed over the years and may be caused by endocrine disrupting chemicals [3, 4] but it can result from anatomical or genetic abnormalities, systemic or neurological diseases, infections, trauma, iatrogenic injury, gonadotoxins and the development of sperm antibodies. In 30–40% of male infertility cases, no cause is identified (idiopathic male infertility) [5]. Male factors may have an influence upon fertilization and embryo development failure, the increase in the risk of idiopathic recurrent miscarriages, autosomal dominant diseases and neurobehavioral disorders in their offspring [6]

Objectives

Methods

Results

Conclusion