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. 2026 Mar 19:S1053-2498(26)01777-8.
doi: 10.1016/j.healun.2026.03.011. Online ahead of print.

Genome-wide association study reveals two novel genetic loci associated with chronic lung allograft dysfunction

Simon Brocard  1 , Vincent Mauduit  2 , Martin Morin  2 , Léo Boussamet  2 , Nayane Dos Santos Brito Silva  3 , Axelle Durand  2 , Pierre Halitim  2 , Benjamin Renaud-Picard  4 , Benjamin Coiffard  5 , Xavier Demant  6 , Loïc Falque  7 , Jérome Le Pavec  8 , Antoine Roux  9 , Thomas Villeneuve  10 , Christiane Knoop  11 , Claire Merveilleux  12 , Mathilde Salpin  13 , Nicolas Carlier  14 , Pierre Antoine Gourraud  2 , Antoine Magnan  9 , David Lair  2 , Laureline Berthelot  2 , Mario Südholt  15 , Nicolas Vince  2 , Adrien Tissot  16 , Sophie Limou  17 ; COLT consortium
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Free article

Genome-wide association study reveals two novel genetic loci associated with chronic lung allograft dysfunction

Simon Brocard et al. J Heart Lung Transplant. .
Free article

Abstract

Background: Chronic lung allograft dysfunction (CLAD) leads to declining respiratory function and high mortality, representing the main barrier to long-term survival in lung transplantation (LT). We performed the first genome-wide association study (GWAS) investigating donor's and recipient's genetic factors associated with CLAD.

Method: We genotyped 392 donor-recipient pairs from the multicentric Cohort in Lung Transplantation. We tested 4.5 million SNPs for association with CLAD using multivariable logistic regression models corrected for age, sex, initial disease and genetic ancestry. Three levels of explanatory variables were separately considered to conduct GWAS: donors-only, recipients-only, and donor-recipient mismatches. We also ran HLA-centric analyses using the same models.

Results: Our analysis confirmed the deleterious impact of HLA allelic and epitopic mismatches on CLAD risk, mostly driven by class I HLA (p=0.004). No significant associations with CLAD were found for donors' genotypes or donor-recipient non-HLA mismatches. We highlighted two independent recipient's loci associated with CLAD, including one protective signal (0.39 in CLAD vs 0.66 in non-CLAD recipients, p-value=5.05x10-7, q-value=0.017, OR=0.35) encompassing the PLXDC2 gene, and one risk signal (0.66 in CLAD vs 0.38 in non-CLAD recipients, p-value=9.86x10-7, q-value=0.017, OR=2.83) encompassing the ZNF518A/BLNK genes. These non-coding SNPs are putative regulatory variants of gene expression. Importantly, our single-cell RNA-sequencing showed a down-regulation of PLXDC2 in fibroblasts and lung epithelium in CLAD vs healthy controls.

Conclusion: This first LT GWAS revealed two candidate loci from the recipient's genome, both biologically relevant for CLAD pathogenesis. Our study calls for larger LT genomic initiatives to increase power for signal discovery.

Keywords: Chronic lung allograft dysfunction; Cohort; DNA biocollection; Donor-recipient pairs; GWAS Genomics; HLA; Lung Transplantation.

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