Semen quality is affected by HLA class I alleles together with sexually transmitted diseases

Abstract

Background: The human leukocyte antigen (HLA) locus includes several genes with key roles in antigen presentation and immune response, some of them inclusively found to be associated with non-obstructive azoospermia. Still, HLA connections to other infertility phenotypes such as semen hyperviscosity (SHV), asthenozoospermia (AST), and oligozoospermia (OLI) have been often neglected.

Objectives: In this work, we aimed to evaluate the association of HLA class I and II genes with SHV, AST, and OLI phenotypes while exploring a possible role in an adaptive immune response to sexually transmitted diseases (STD).

Materials and methods: Whole-exome sequencing was performed in a Portuguese cohort of 71 infertility cases and 68 controls, followed by HLA typing using a specific software-HLA*PRG:LA tool. Molecular screenings of seven STD were carried out in a subset of 72 samples (30 cases and 42 controls).

Results: Statistical tests uncovered three protective alleles: HLA-A*11:01, associated with all forms of male infertility (p = 0.0006); HLA-DQB1*03:02 with SHV and OLI (P_SHV = 0.0303, P_OLI = 0.0153); and HLA-A*29:02 with OLI (p = 0.0355), which was found to interfere in sperm number together with HPV (p = 0.0313). Five risk alleles were also identified: two linked with SHV (HLA-B*50:01, p = 0.0278; and HLA-C*06:02, p = 0.0461), another one with both SHV and OLI (HLA-DQA1*05:01, P_SHV = 0.0444 and P_OLI =0.0265), and two with OLI (HLA-C*03:03, p = 0.0480; and HLA-DQB1*03:01, p = 0.0499). Here, HLA-C*03:03 carriers tend to be HPV infected.

Conclusions: The application of HLA*PRG:LA tool to the study of male infertility provided novel insights for an HLA correlation with semen quality, namely among SHV and OLI phenotypes. The discovery of an HLA-A*29:02/HPV crosstalk, together with former reports of HLA alleles conferring resistance-susceptibility to diverse human pathogens, raises the hypothesis of a mechanistic link between male infertility, HLA polymorphism, and host response to STD.

Keywords: HPV; HLA-A; association study; male infertility; oligozoospermia; semen hyperviscosity.

Figure 1 -

Risk effect analysis for HLA alleles in male infertility. The relative position of HLA genes (central diagram) is shown along with forest plots for alleles presenting significant associations with male infertility (P < 0.05). Each allele plot shows the Odd Ratios (OR) for four comparisons performed: Controls vs. oligozoospermia (OLI); Controls vs. asthenozoospermia (AST); Controls vs. semen hyperviscosity (SHV) and Controls vs. all cases. The dashed black line represents OR = 1. For each comparison OR values and confidence intervals are shown by a dot and a line, respectively, and where color denotes the allele effect: black – none (non-significant); blue – protective (significant); red – risk (significant).

Figure 2 -

Evaluation of amino acid composition of HLA-A, HLA-B, HLA-DQA1 and HLA-DQB1 alleles associated to male infertility (P < 0.05). Frequencies of the different residues encoded by HLA alleles showing significant results for semen hyperviscosity (SHV), asthenozoospemia (AST) or oligozoospermia (OLI). *P < 0.05; **P < 0.01; ***P < 0.001.

Figure 3 -

Effect of STD agents in sperm concentration. Group differences between sperm number and STD (all identified pathogens), Chlamydia trachomatis or human papilloma virus (HPV) presence/absence are shown.

Figure 4 -

Interaction analysis of HLA-A*29:02 allele and human papilloma virus (HPV) in sperm concentration. Mean sperm number and 95% confidence intervals are shown for four combinations according to allele presence or absence and to HPV infection status (HPV+ or HPV-). *P < 0.05; **P < 0.01; ***P < 0.001.