Lung transplantation for idiopathic pulmonary fibrosis enriches for individuals with telomere-mediated disease

Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is the most common indication for lung transplantation in North America and variants in telomere-maintenance genes are the most common identifiable cause of IPF. We reasoned that younger IPF patients are more likely to undergo lung transplantation and we hypothesized that lung transplant recipients would be enriched for individuals with telomere-mediated disease due to the earlier onset and more severe disease in these patients.

Methods: Individuals with IPF who underwent lung transplantation or were evaluated in an interstitial lung disease specialty clinic who did not undergo lung transplantation were examined. Genetic evaluation was completed via whole genome sequencing (WGS) of 426 individuals and targeted sequencing for 5 individuals. Rare variants in genes previously associated with IPF were classified using the American College of Medical Genetics guidelines. Telomere length from WGS data was measured using TelSeq software. Patient characteristics were collected via medical record review.

Results: Of 431 individuals, 149 underwent lung transplantation for IPF. The median age of diagnosis of transplanted vs non-transplanted individuals was significantly younger (60 years vs 70 years, respectively, p<0.0001). IPF lung transplant recipients (IPF-LTRs) were twice as likely to have telomere-related rare variants compared to non-transplanted individuals (24% vs 12%, respectively, p=0.0013). IPF-LTRs had shorter telomeres than non-transplanted IPF patients (p=0.0028) and >85% had telomeres below the age-adjusted mean. Post-transplant survival and CLAD were similar amongst IPF-LTRs with rare variants in telomere-maintenance genes compared to those without, as well as in those with short telomeres versus longer telomeres.

Conclusions: There is an enrichment for telomere-maintenance gene variants and short telomeres among IPF-LTRs. However, transplant outcomes of survival and CLAD do not differ by gene variants or telomere length within IPF-LTRs. Our findings support individual with telomere-mediated disease should not be excluded from lung transplantation and focusing research efforts on therapies directed toward individuals with short-telomere mediated disease.

Keywords: CLAD; IPF; genetic testing; telomerase; telomere length; transplant.

Figure 1.. Transplant recipients are enriched for patients with rare variants in telomere-maintenance genes.

A) Proportions of transplanted and non-transplanted individuals with variants in the indicated genes. B) Age at diagnosis by gene containing rare variant. Median is depicted by black bar. None of the groups were significantly different by one-way ANOVA analysis. Two individuals carried variants in more than one gene and are included in both groups. C-D) Kaplan-Meier analysis of survival (C; HR 1.39, 95% CI 0.78-2.47, P=0.26) and onset of CLAD (D; HR 0.95, 95% CI 0.46-2.00, P=0.84) in transplant recipients based on identification of rare variants in telomere-associated genes (Log-rank test).

Figure 2.. Telomere length measurement and clinical outcomes of transplant recipients based on genetic findings.

A) Scatter plot of telomere length and age from 903 non-ILD individuals showing age-associated decline in telomere length. B) Nomogram lines depicting the distribution of telomere lengths at each age based on data in (A). C) Telomere length and age of lung transplant recipients. Black dots indicated patients with no genetic finding and red dots are those where rare variants were identified. D) Deviation from the age-adjusted 50^th percentile for patients with and without rare variants in telomere-associated genes. Student t test was used for comparison of means. Median and standard deviation is shown for each group. E) Deviation from age adjusted 50^th percentile in transplanted (TXR) and non-transplanted patients. One-way ANOVA with Tukey’s post-hoc test was used for comparison of means. Median and standard deviation is shown for each group. F-G) Kaplan-Meier analysis of survival (F; HR 0.86, 95% CI 0.48-1.53, P=0.62) and onset of CLAD (G; HR 0.73, 95% CI 0.36-1.46, P=0.50) in transplant recipients stratified by telomere length (Log-rank test). **P < 0.01, ***P < 0.001, ****P < 0.0001.