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Genome-Wide Association Study of Chronic Lung Allograft Dysfunction
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Edité par CCSD -
International audience. 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). The lung graft survival remains limited with only 50.6% survival at 5 years post-transplantation. The greatest limitation to long-term survival is the development of chronic lung allograft dysfunction (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) and regroups 3 phenotypes: BOS (bronchiolitis obliterans syndrome) is a predominantly obstructive ventilatory syndrome; RAS exhibits a restrictive pattern; and a mixed obstructive and restrictive pattern. There is an essential need for better understanding the molecular mechanisms involved in the CLAD phenotype’s pathophysiology. Here, we performed the first genome-wide association study investigating genetic factors associated with CLAD. 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 (900K 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 7M SNPs for association with CLAD using logistic regression models corrected for age, sex and genetic ancestry. We did not identify any significant signal between donors’ genotypes and CLAD. Thirteen SNPs were significantly associated with CLAD in European recipients (P<5x10-8). Interestingly, one locus encompasses PLXDC2 (P=2.18x10-9, OR=0.39), coding for a protein previously associated with the risk for bronchopulmonary dysplasia. The other locus involves CCDC60 (P=3.47x10-9, OR=0.38), which is highly expressed in the trachea and in epithelial cells from the upper respiratory system. Here, we unveil the initial Genome-Wide Association Study conducted in lung transplantation, displaying results that are biologically significant. In the coming months, we intend to further investigate the roles of HLA, mismatches and more refined CLAD phenotypes such as BOS/RAS and other factors.
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