Analysis of protein-altering variants in telomerase genes and their association with MUC5B common variant status in patients with idiopathic pulmonary fibrosis: a candidate gene sequencing study

Dressen, Amy; Abbas, Alexander R.; Cabanski, Christopher R.; Reeder, Janina; Ramalingam, Thirumalai R.; Neighbors, Margaret; Bhangale, Tushar; Brauer, Matthew J.; Hunkapiller, Julie; Reeder, Jens; Mukhyala, Kiran; Cuenco, Karen T.; Tom, Jennifer; Cowgill, Amy; Vogel, Jan; Forrest, William F.; Collard, Harold R.; Wolters, Paul J.; Kropski, Jonathan A.; Lancaster, Lisa; Blackwell, Timothy S.; Arron, Joseph R.; Yaspan, Brian L.

doi:10.1016/s2213-2600(18)30135-8

Cited by 147 publications

(161 citation statements)

References 52 publications

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“…In the UUS study, cases were recruited from across the USA, UK and Spain and controls were selected from UK Biobank to follow a similar sex and smoking distribution seen in the IPF cases (Appendix). The Genentech study consisted of cases from three IPF clinical trials and controls from four non-IPF clinical trials that have been previously described (Appendix) 15 . All five studies restricted to unrelated individuals of European ancestry and we applied stringent quality control measures (Appendix).…”

Section: Methodsmentioning

confidence: 99%

Genome-wide association study of susceptibility to idiopathic pulmonary fibrosis

Guillén‐Guío

Oldham

et al. 2019

Preprint

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Rationale: Idiopathic pulmonary fibrosis (IPF) is a complex lung disease characterised by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. The mechanisms by which this arises are poorly understood and it is likely that multiple pathways are involved. The strongest genetic association with IPF is a variant in the promoter of MUC5B where each copy of the risk allele confers a five-fold risk of disease. However, genome-wide association studies have reported additional signals of association implicating multiple pathways including host defence, telomere maintenance, signalling and cell-cell adhesion. Objectives:To improve our understanding of mechanisms that increase IPF susceptibility by identifying previously unreported genetic associations. Methods and measurements:We performed the largest genome-wide association study undertaken for IPF susceptibility with a discovery stage comprising up to 2,668 IPF cases and 8,591 controls with replication in an additional 1,467 IPF cases and 11,874 controls. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF. Main results:We identified and replicated three new genome-wide significant (P<5×10 −8 ) signals of association with IPF susceptibility (near KIF15, MAD1L1 and DEPTOR) and confirm associations at 11 previously reported loci. Polygenic risk score analyses showed that the combined effect of many thousands of as-yet unreported IPF risk variants contribute to IPF susceptibility. Conclusions:Novel association signals support the importance of mTOR signalling in lung fibrosis and suggest a possible role of mitotic spindle-assembly genes in IPF susceptibility.

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Section: Methodsmentioning

confidence: 99%

Genome-wide association study of susceptibility to idiopathic pulmonary fibrosis

Guillén‐Guío

Oldham

et al. 2019

Preprint

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“…These mutations have been associated with an early aging phenotype and a spectrum of often overlapping diseases, including bone marrow failure, blood and solid tumor malignancies, pulmonary fibrosis, liver cirrhosis, hair graying, and skin pigmentation . As the role of each component of the telomerase complex becomes clearer, new gene candidates become available to explore their relationship to shortened telomeres and organ dysfunction …”

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“…(1) As the role of each component of the telomerase complex becomes clearer, new gene candidates become available to explore their relationship to shortened telomeres and organ dysfunction. (2) Liver cirrhosis leads to varying degrees of pancytopenia through multiple known mechanisms, including splenic sequestration, decreased thrombopoietin production, nutritional deficiencies, and gastrointestinal bleeding. The potential contribution of telomerase complex gene variants to cytopenias could have significant implications for these patients after liver transplantation, as they take myelosuppressive medications to prevent transplant rejection and infection.…”

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Telomerase Variants in Patients with Cirrhosis Awaiting Liver Transplantation

et al. 2019

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Telomeres are repetitive DNA sequences that protect the ends of linear chromosomes, and they are maintained by a ribonucleoprotein complex called telomerase. Variants in genes encoding for telomerase components have been associated with a spectrum of disease in the lung, skin, bone marrow, and liver. Mutations in the telomerase reverse transcriptase and telomerase RNA component genes have been observed at a higher prevalence in patients with liver disease compared with the general population; however, the presence of variants in other components of the telomerase complex and their impact on clinical outcomes has not been explored. We evaluated 86 patients with end‐stage liver disease for variants in an expanded panel of eight genes, and found that 17 patients (20%) had likely deleterious variants by in silico analysis. Seven unique likely deleterious variants were identified in the regulator of telomere elongation helicase 1 ( RTEL1 ) gene that encodes for a DNA helicase important in telomere maintenance and genomic stability. In gene burden association analysis of their clinical data, the presence of any RTEL1 variant was associated with a 29% lower baseline white blood cell count (95% confidence interval [CI], ‐7% to ‐46%; P Value = 0.01) compared with patients without RTEL1 variants, and the presence of any exonic missense RTEL1 variant was associated with a 42% lower baseline platelet count (95% CI, ‐5% to ‐65%: P Value = 0.03). The presence of any telomerase variant was associated with an increased number of readmissions within 1 year after transplantation demonstrated by an incident rate ratio (IRR) of 3.15 (95% CI, 1.22 to 8.57). No association with survival was observed. Conclusion : Among patients who underwent liver transplantation, the presence of any exonic missense variant was associated with a longer postoperative length of stay with an IRR of 2.16 (95% CI, 1.31 to 3.68).

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“…proposed TRG genetic testing after TL measurement and identification of shortened TL <10th percentile in clinical practice . However, two recent studies show that ‘rare’ TRG variants may not be so rare after all, even in sporadic IPF: TRG variants were identified in 149 (9%) of 1739 IPF patients included in four clinical trials (INSPIRE, CAPACITY, ASCEND and RIFF) and in 29 (11.3%) of a cohort of 262 IPF patients before lung transplantation, although a younger age than observed in usual IPF cohorts was seen in this study …”

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“…However, interpretation of sequence variants should follow the consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology . Indeed, it should be noted that the evidence for putative pathogenicity of the retained variants was not precisely assessed in one study, leading to the inclusion of three variants classified as polymorphisms in telomerase databases: TERC r.58G>A, TERC r.228G>A and TERT p.His412Tyr.…”

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Pulmonary fibrosis: Genetic analysis of telomere‐related genes, telomere length measurement‐or both?

2018

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Analysis of protein-altering variants in telomerase genes and their association with MUC5B common variant status in patients with idiopathic pulmonary fibrosis: a candidate gene sequencing study

Abstract: Genentech, National Institutes of Health, Francis Family Foundation, Pulmonary Fibrosis Foundation, Nina Ireland Program for Lung Health, US Department of Veterans Affairs.

Cited by 147 publications

References 52 publications

Genome-wide association study of susceptibility to idiopathic pulmonary fibrosis

Genome-wide association study of susceptibility to idiopathic pulmonary fibrosis

Telomerase Variants in Patients with Cirrhosis Awaiting Liver Transplantation

Pulmonary fibrosis: Genetic analysis of telomere‐related genes, telomere length measurement‐or both?

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