The Genetics Research Of Telomerase Gene Mutations With IPF In Nanjing Han Population Of China

IPF is the most common form of idiopathic interstitial pneumonia, which is characterized by progressive dyspnea and ultimately respiratory failure. It is a fatal and devastating disease with a median survival time of 2 to 3 years from diagnosis. No clearly effective treatment exists, leaving lung transplantation as currently the only avenue for improving survival. Obtaining a better understanding of IPF pathogenesis may provide important clues required for ultimately developing a therapy for the disease. Important advancements in molecular genetics research in recent years have improved possibilities for solving the pathogenic mechanisms underlying IPF. Hereditary factors likely play a role, since as many as 19% of IPF cases have some familial linkage, where at least two first- or second-degree family members develop the disease (called familial pulmonary fibrosis, or FPF). Inheritance appears to be autosomal dominant with variable penetrance.Telomerase is a remarkable enzyme that adds telomere repeats to the ends of chromosome. Telomerase has two essential components:TERT, the telomerase reverse transcriptase, and TERC, a specialized RNA that contains a template for telomere repeat addition. TERT uses the template within TERC to add new (TTAGGG) repeats onto the 3_ end of chromosomes, maintaining the integrity and stability of genome and ensures the transmission of the total length of the telomere in each cellular division. IPF is the most frequent manifestation of telomerase-associated disease. Mutations in the essential genes coding for the enzyme telomerase are the most commonly identified genetic risk factors in IPF and approximately 8 to 18% of FPF have autosomal dominant mutations in one of the two genes encoding TERT or TERC. Telomere shortening is believed to play a key role in these mutations. Some previous studies reported that telomere shortening is a risk factor for the development of IPF. However, in China, no genetic studies have been carried out in IPF and few studies on telomere length as an independent prognostic factor for IPF or whether telomere length has a relationship with the disease stage and radiographic pattern.We collected detailed medical histories and DNA samples from 123 IPF patients seen at the Affiliated Drum Tower Hospital of Nanjing University Medical School. The diagnosis was made based on criterion for diagnosis of IPF in absence of surgical lung biopsy recommended by the American Thoracic Society and the European Respiratory Society (ATS\ERS). All patients were sporadic pulmonary fibrosis (SPF), who denied family history. We screened all patients for TERT and TERC variants, and extended this screen to first-degree relatives of IPF patients and examined telomere length in lymphocytes. For each patient, medical records were thoroughly reviewed and clinic data were extracted. Outcome was defined to be dead during follow up. Based on recommendations made by ATS\ERS in 2000, the HRCT appearances of IPF were categorized as UIP pattern and possible UIP pattern.Therefore, we identified six novel telomerase gene mutations in individuals diagnosed with SPF in the Chinese Han population. The individuals with TERT/TERC mutations had shorter telomeres compared with those harboring normal TERT/TERC genes. Shorter telomere length was associated with chest HRCT pattern and outcome in IPF. Old and chest HRCT pattern were independent risk factors for the outcome of IPF.