Examining extended human leukocyte antigen-G and HLA-F haplotypes: the HLA-G UTR-4 haplotype is associated with shorter time to pregnancy in an infertility treatment setting when both female and male partners are carriers

Fertil Steril. 2020 Sep;114(3):628-639. doi: 10.1016/j.fertnstert.2020.04.052.

Abstract

Objective: To study the impact of extended human leukocyte antigen (HLA)-G and HLA-F haplotypes on time to pregnancy as measured by the number of treatment cycles in a cohort of couples in infertility treatment.

Design: Prospective cohort study of couples undergoing infertility treatment.

Setting: University hospital.

Patient(s): A cohort of 127 couples and four single women in infertility treatment.

Intervention(s): Next-generation sequencing of the HLA-G gene and genotyping of three HLA-F locus single-nucleotide polymorphisms (SNPs).

Main outcome measure(s): Extended HLA-F.HLA-G haplotypes, HLA-G promoter haplotypes and HLA-G 3'UTR haplotypes and their association with time to pregnancy as measured by number of treatment cycles until achievement of pregnancy with a live birth. Linkage disequilibrium between HLA-G variations and three HLA-F locus SNPs that impact time to pregnancy.

Result(s): The effect of the HLA-G 3'UTR haplotype, UTR-4, was significantly increased, or modified, if the partner was a carrier compared to being a noncarrier. Extended HLA-F.HLA-G haplotypes, HLA-G promoter haplotypes, and the HLA-G 14 bp indel of the female partners were not associated with time to pregnancy. However, a trend for an association of the HLA-G 14bp insertion allele with a higher frequency of miscarriage than the 14bp deletion allele was observed. Certain HLA-G variations are in linkage disequilibrium with three HLA-F locus SNPs that influence time to pregnancy.

Conclusion(s): HLA-G UTR-4 is significantly associated with time to pregnancy in couples undergoing infertility treatment. The findings could imply that both male and female HLA class Ib genetics have clinical relevance in reproduction.

Keywords: HLA-F; HLA-G; Infertility; assisted reproduction technologies; gene variation.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Denmark
  • Female
  • HLA-G Antigens / genetics*
  • HLA-G Antigens / metabolism
  • Haplotypes*
  • Heterozygote*
  • High-Throughput Nucleotide Sequencing
  • Histocompatibility Antigens Class I / genetics*
  • Histocompatibility Antigens Class I / metabolism
  • Humans
  • Infertility / genetics*
  • Infertility / immunology
  • Infertility / physiopathology
  • Infertility / therapy
  • Linkage Disequilibrium
  • Male
  • New Zealand
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Pregnancy
  • Pregnancy Rate
  • Prospective Studies
  • Reproductive Techniques, Assisted*
  • Time Factors
  • Time-to-Pregnancy / genetics*
  • Treatment Outcome

Substances

  • 3' Untranslated Regions
  • HLA-F antigens
  • HLA-G Antigens
  • Histocompatibility Antigens Class I