Idiopathic pulmonary fibrosis (IPF) is an age-related disease featuring progressive lung scarring. To elucidate the molecular basis of IPF, we performed exome sequencing of familial pulmonary fibrosis kindreds. Gene burden analysis comparing 78 European cases and 2,816 controls implicated PARN, an exoribonuclease with no prior connection to telomere biology or disease, with five novel heterozygous damaging mutations in unrelated cases and none in controls (P-value = 1.3 × 10−8); mutations were shared by all affected relatives (odds in favor of linkage = 4,096:1). RTEL1, an established locus for dyskeratosis congenita, harbored significantly more novel damaging and missense variants at conserved residues in cases than controls (P = 1.6 × 10−6). PARN and RTEL1 mutation carriers had shortened leukocyte telomere lengths and epigenetic inheritance of short telomeres was seen in family members. Together these genes explain ~7% of familial pulmonary fibrosis and strengthen the link between lung fibrosis and telomere dysfunction.

A constellation of related genetic diseases are caused by defects in the telomere maintenance machinery. These disorders, often referred to as telomeropathies, share symptoms and molecular mechanisms, and mounting evidence indicates they are points along a spectrum of disease. Several new causes of these disorders have been recently discovered, and a number of related syndromes may be unrecognized telomeropathies. Progress in the clinical understanding of telomeropathies has in turn driven progress in the basic science of telomere biology. In addition, the pattern of genetic anticipation in some telomeropathies generates thought-provoking questions about the way telomere length impacts the course of these diseases.

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BackgroundLoss of function in genes required for telomere maintenance result in disorders known as telomeropathies, which are characterized by a pattern of symptoms including generalized and specific lymphocytopenias as well as very short telomere length and disease anticipation.MethodsBecause human LARP7 is the most likely ortholog of the Tetrahymena p65 protein, which is required for telomerase activity in that organism, we investigated the effects of LARP7 silencing in human cells as well as in two distinct families with Alazami syndrome (loss of function of LARP7).ResultsDepletion of LARP7 caused a reduction in telomerase enzymatic activity and progressively shorter telomeres in human cancer cell lines. Alazami syndrome patients from two separate cohorts exhibited very short lymphocyte telomeres. Further, wild-type offspring of LARP7 mutant individuals also had very short telomeres, comparable to what is observed in telomerase (hTERT) mutant cohorts.ConclusionsTogether, these experiments demonstrate that in addition to the readily apparent developmental disorder associated with LARP7 deficiency, an underlying telomeropathy exists even in unaffected siblings of these individuals.

Telomere length shortens with aging, and short telomeres have been linked to a wide variety of pathologies. Previous studies suggested a discrepancy in age-associated telomere shortening rate estimated by cross-sectional studies versus the rate measured in longitudinal studies, indicating a potential bias in cross-sectional estimates. Intergenerational changes in initial telomere length, such as that predicted by the previously described effect of a father’s age at birth of his offspring (FAB), could explain the discrepancy in shortening rate measurements. We evaluated whether changes occur in initial telomere length over multiple generations in three large datasets and identified paternal birth year (PBY) as a variable that reconciles the difference between longitudinal and cross-sectional measurements. We also clarify the association between FAB and offspring telomere length, demonstrating that this effect is substantially larger than reported in the past. These results indicate the presence of a downward secular trend in telomere length at birth over generational time with potential public health implications.

Background: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting women of reproductive age. Previous studies have identified genetic variants associated with PCOS identified by different diagnostic criteria. The Rotterdam Criteria is the broadest and able to identify the most PCOS cases. Objectives: To identify novel associated genetic variants, we extracted PCOS cases and controls from the electronic health records (EHR) based on the Rotterdam Criteria and performed a genome-wide association study (GWAS). Study Design: We developed a PCOS phenotyping algorithm based on the Rotterdam criteria and applied it to three EHR-linked biobanks to identify cases and controls for genetic study. In discovery phase, we performed individual GWAS using the Geisinger's MyCode and the eMERGE cohorts, which were then meta-analyzed. We attempted validation of the significantly association loci (P<1x10-6) in the BioVU cohort. All association analyses used logistic regression, assuming an additive genetic model, and adjusted for principal components to control for population stratification. An inverse-variance fixed effect model was adopted for meta-analyses. Additionally, we examined the top variants to evaluate their associations with each criterion in the phenotyping algorithm. We used STRING to identify protein-protein interaction network. Results: We identified 2,995 PCOS cases and 53,599 controls in total (2,742 cases and 51,438 controls from the discovery phase; 253 cases and 2,161 controls in the validation phase). GWAS identified one novel genome-wide significant variant rs17186366 (OR=1.37 [1.23,1.54], P=2.8x10-8) located near SOD2. Additionally, two loci with suggestive association were also identified: rs113168128 (OR=1.72 [1.42,2.10], P=5.2 x10-8), an intronic variant of ERBB4 that is independent from the previously published variants, and rs144248326 (OR=2.13 [1.52,2.86], P=8.45x10-7), a novel intronic variant in WWTR1. In the further association tests of the top 3 SNPs with each criterion in the PCOS algorithm, we found that rs17186366 was associated with polycystic and hyperandrogenism, while rs11316812 and rs144248326 were mainly associated with oligomenorrhea or infertility. Besides ERBB4, we also validated the association with DENND1A1. Conclusion: Through a discovery-validation GWAS on PCOS cases and controls identified from EHR using an algorithm based on Rotterdam criteria, we identified and validated a novel association with variants within ERBB4. We also identified novel associations nearby SOD2 and WWTR1. These results suggest the eGFR and Hippo pathways in the disease etiology. With previously identified PCOS-associated loci YAP1, the ERBB4-YAP1-WWTR1 network implicates the epidermal growth factor receptor and the Hippo pathway in the multifactorial etiology of PCOS.

Most tumors circumvent telomere-length imposed replicative limits through expression of telomerase, the reverse transcriptase that maintains telomere length. Substantial evidence that AKT activity is required for telomerase activity exists, indicating that AKT inhibitors may also function as telomerase inhibitors. This possibility has not been investigated in a clinical context despite many clinical trials evaluating AKT inhibitors. We tested if Perifosine, an AKT inhibitor in clinical trials, inhibits telomerase activity and telomere maintenance in tissue culture and orthotopic xenograft models as well as in purified CLL samples from a phase II Perifosine clinical trial. We demonstrate that Perifosine inhibits telomerase activity and induces telomere shortening in a wide variety of cell lines in vitro, though there is substantial heterogeneity in long-term responses to Perifosine between cell lines. Perifosine did reduce primary breast cancer orthotopic xenograft tumor size, but did not impact metastatic burden in a statistically significant manner. However, Perifosine reduced telomerase activity in four of six CLL patients evaluated. Two of the patients were treated for four to six months and shortening of the shortest telomeres occurred in both patients' cells. These results indicate that it may be possible to repurpose Perifosine or other AKT pathway inhibitors as a novel approach to targeting telomerase.