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Genome-Wide Association Study of Chronic Lung Allograft Dysfunction
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Edité par CCSD -
International audience. Background: 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), but graft survival remains limited with only 63% survival at 5 years post-transplantation. The greatest limitation to long-term survival is the development of chronic lung allograft dysfunction (CLAD) which affects arounds 50% of recipients after 5 years. There is an essential need for better understanding the molecular mechanisms involved in the CLAD phenotype’s pathophysiology. Methods: We performed the first genome-wide association study GWAS investigating genetic factors associated with CLAD. CLAD is defined by a >=20% decline in measured forced expiratory volume from the baseline level (3 months after transplant in the absence of infection or another identifiable cause). We genotyped a subset of 392 LT donor-recipient pairs from the COLT multicentric cohort (Cohort in Lung Transplantation) using the Affymetrix Axiom PRMA microarray (900,000 SNPs). Our genetic cohort represents an accurate snapshot of the entire COLT cohort as no variable (e.g. age, sex, initial respiratory disease, survival rate) significantly diverged from the global cohort (p>0.05). After quality controls and SNP imputation, we tested 7 million SNPs for association with CLAD using multivariate logistic regression models corrected for age, sex and genetic ancestry. Results: We did not observe any significant association between the donors’ genotypes and the CLAD development. However, we tested 54 CLAD (BOS=34, RAS=9 and mixte=11) against 160 stable recipients and we identified four SNPs significantly associated with CLAD in European recipients (p<5x10-8). Interestingly, we found a signal in a gene encoding a protein previously associated with the risk for bronchopulmonary dysplasia. Recipients with CLAD exhibited a lower allelic frequency (34%) for this genetic locus than recipients without CLAD (66%), suggesting a protective role for this allele against the development of CLAD. Conclusions: Here, we unveiled the first GWAS conducted in lung transplantation, displaying biologically relevant results from the recipient’s genome. We will next jointly investigate the donor and recipient’s genomes to assess HLA and non-HLA mismatches that might contribute to CLAD. Further investigations into the functional implications of these genetic variants could provide valuable insights into pathogenesis and potential therapeutic targets for CLAD.
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