Rare Gene Variants Linked to Worse Lung Transplant Outcomes in PF Patients

Rare variants in genes that regulate the end regions of chromosomes — called telomeres — are linked with worse survival rates after lung transplant in pulmonary fibrosis (PF) patients, a study suggests.

The study, “Lung Transplant Outcomes in Pulmonary Fibrosis Patients with Telomere-Related Gene Variants” was published in the journal Chest.

Lung transplant is a frequently recommended treatment option for PF. However, PF patients are known to have worse survival rates after transplant compared to other diseases, with aging being a contributor factor.

Recent studies have suggested a role for rare genetic variants in PF, in particular in a gene that encodes an enzyme called telomerase. Telomerase is a protein that controls the length of telomeres — specialized structures at the ends of chromosomes that protect them from deterioration or fusion with neighboring chromosomes. Telomeres are know to get shorter with cell division.

Researchers therefore hypothesized that variations in telomere-related genes, such as TERT, RTEL1, and PARN could have an impact on lung transplant outcomes in PF patients.

To test their hypothesis, the team analyzed a cohort of 262 adult PF patients who underwent a first lung transplant at Duke University Medical Center. Patients were followed for a median period of 2.8 years after lung transplant.

A prior genetic analysis revealed that 31 of the 262 patients (11.8%) carried rare genetic variants in the TERT, RTEL1, or PARN genes, which were linked with PF risk — 13 had variants in the TERT gene, 10 had variants in the RTEL1 gene, and eight had variants in the PARN gene.

In total, 64% of patients with TERT, RTEL1 or PARN gene variants, and 77% of patients without these genetic alterations, experienced at least one episode of post-transplant acute rejection in the first year after the procedure.

However, the time that some transplanted patients took to develop chronic lung allograft dysfunction (CLAD) — problems with the newly transplanted lung — was significantly shorter for patients with genetic variants in the telomere-related genes, compared with PF patients without these variants. In fact, CLAD was the leading cause of death among PF cases with genetic alterations, accounting for 39% of the deaths.

The estimated death rates at 5 years post-transplant were 58% for patients with TERT, RTEL1, or PARN gene variants, compared to 43% in those without. This higher risk of death was still maintained for patients with the gene variants when the data was adjusted for factors such as age, sex, and type of transplant (single, bilateral, or multi-organ).

A higher number of patients with TERT, RTEL1, or PARN variants also developed anemia in the first year after transplant.

Researchers reasoned that patients with TERT, RTEL1 or PARN variations could have lower levels of immunosuppression, which in turn could lead to transplant failure. Also, they believe that these patients are more prone to cytomegalovirus (CMV) infection, which was previously linked with an increased risk of CLAD and death in several studies.

Overall, the results “suggest that rare TERT, RTEL1, or PARN variants represent a novel genetic factor that contributes to poor outcomes after lung transplant among PF patients,” researchers said, adding that “this effect is independent of factors already known to impact post-transplant outcomes in this population including older age and type of transplant.”

According to the team, the results support the potential usefulness of including a genetic screening for PF patients in future clinical trials to better tailor treatment interventions for patients with genetic variants in telomere-related genes.