# Immunogenomic exploration in a large lung transplantation genetic cohort reveals a chronic lung allograft dysfunction association with HLA-DQB1*03:01

Simon Brocard, Assane Sylla, Nayane dos Santos Brito Silva, Pierre-antoine Gourraud, Mario Südholt, N. Vince, Sophie Limou, Colt Consortium

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## ► To cite this version:

Simon Brocard, Assane Sylla, Nayane dos Santos Brito Silva, Pierre-antoine Gourraud, Mario Südholt, et al.. Immunogenomic exploration in a large lung transplantation genetic cohort reveals a chronic lung allograft dysfunction association with HLA-DQB1*03:01. EFI 2025 - 2ème Conférence Internationale sur l'Economie et la Finance Internationale, May 2025, Prague, Czech Republic. 2025. hal-05095900

HAL Id: hal-05095900

https://hal.science/hal-05095900v1

Submitted on 22 Jul 2025

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## Immunogenomic exploration in a large lung transplantation genetic cohort

S. Brocard¹, A. Sylla¹, N. Dos Santos¹, PA. Courraud¹, M. Südholt¹, A. Tissot¹, N. Vince¹, S. Limou¹ and the COLT Consortium

¹Nantes Université, CHU Nantes, Centrale Nantes, Inserm, Center for Research in Transplantation and Translational Immunology CR2TI, UMR 1064, Nantes, France;

### CONTEXT

**Chronic respiratory diseases** are among the leading causes of morbidity and mortality worldwide with **3.3 million deaths each year**. For patients with end-stage lung disease, the only viable option is **lung transplantation (LT)**. However, **chronic lung allograft dysfunction (CLAD)** develops in half of the recipients within 5 years after LT and remains the **major barrier for long-term survival**. There is therefore an essential need for better understanding the molecular **mechanisms involved in CLAD pathophysiology**. The impact of **HLA mismatches** in LT outcomes remains uncertain, with previous studies yielding conflicting results (Opelz et al., Transplantation 2010). However, more recent data suggest a **potential risk of CLAD** (Yamada et al., Thoracic Surgery 2018).

### METHODS

Whole-genome genotypes for **392** LT pairs (n=900K SNPs) → **GenCOLT**

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We imputed the **HLA** alleles from these SNPs using **HIBAG** to achieve high-resolution typing. A total of 5 genes (**HLA-A**, **HLA-B**, **HLA-C**, **HLA-DRB1**, and **HLA-DQB1**) were analyzed using multivariate logistic regression models, adjusted for **age**, **sex**, **ancestry**, and **the initial disease**. A significance threshold of $10^{-4}$ was applied.

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1,200 patients

HLA genetic association study on CLAD

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Clinical follow-up data (mean=67 months, n=80 variables)

COLT is a **French and Belgian multicentric cohort of LT created in 2009**.

Our genetic cohort (GenCOLT) represents an accurate snapshot of the entire COLT cohort (Brocard et al., EJHG 2018).

### RESULTS

Projection of GenCOLT with the 1,000 Genomes Project reference individuals

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Our COLT samples displayed widespread distribution across these populations, with a notable concentration among individuals of European descent: **90.8% of COLT donors and recipients exhibit European ancestry.**

HLA association with CLAD

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We did not observe any significant association with CLAD for the recipients or from the donors' HLA alleles ($P > 10^{-4}$). Our top signal was **HLA-C*02:02** in recipients ($P = 1.4 \times 10^{-2}$, OR=0.12). Our results suggest a call for further research in larger cohorts to **increase the statistical power** for discovery.

### CONCLUSIONS

* We were therefore unable to demonstrate the impact of HLA mismatches on the development of CLAD.

* However, the previous analyses did not consider the ancestry of the patients, here we show that by adjusting the regression models for ancestry in addition to the classic covariates such as age, sex and initial disease, the impact of HLA alleles on CLAD is not demonstrated.

* Understanding of HLA involvement in allograft injury risk could pave the way for innovative, personalized interventions, aiming to improve long-term outcomes for LT.