HLA-G +3196 Polymorphism as a Risk Factor for Cell Mediated Rejection Following Heart Transplant

Hum Immunol. 2020 Apr;81(4):134-140. doi: 10.1016/j.humimm.2020.01.002. Epub 2020 Jan 9.

Abstract

Background: Rejection is a leading cause of mortality following heart transplantation. Human leukocyte antigen-G (HLA-G) is an immune checkpoint which dampens the immune response. Reports suggest elevated HLA-G expression is associated with reduced allograft rejection. Our objective was to evaluate HLA-G polymorphisms and cell mediated rejection (CMR) development.

Methods: Recipients (n = 123) were genotyped to identify relevant HLA-G polymorphisms in the 5'regulatory (-725, -201), 3'untranslated (+3197, +3187, +3142, 14-bp indel) and coding regions (haplotypes 1-6). CMR was evaluated via endomyocardial biopsy (grade ≥ 2R). Univariate/adjusted analyses were conducted via Kaplan Meier and proportional hazard models.

Results: Mean recipient age was 48 (±12) years, with a median time to CMR of 4.6 years. 55 (45%) recipients had a biopsy grade ≥ 2R. Adjusted analysis revealed the +3196 G allele as a risk factor for CMR (p = 0.03). Compared to the minor GG genotype, CG had a 47.2% reduction in CMR risk (HR[95% CI] = 0.528 [0.235, 1.184]), while CC had a 66.9% reduction (0.331 [0.144, 0.761]). The recessive effect significantly increased CMR likelihood (2.388 [1.128, 5.059], p = 0.02).

Conclusion: The HLA-G +3196 G allele was identified as a risk factor for CMR diagnosis. HLA-G may have a role in therapeutic/diagnostic strategies against transplant rejection.

Keywords: Heart transplantation; Immune checkpoint; Major histocompatibility complex; Polymorphism; Rejection.