Genetic Analysis Of Telomere And Its Association Study With Lung Cancer

Part 1 A Genome-Wide Association Study Identifies a Locus on TERT for Mean Telomere Length in Han ChineseLeukocyte telomere length (LTL) is a predictor of aging and a number of age-related diseases. Telomere length is important in determining telomere function, whose dysregulation can lead to cell death, cell senescence, or abnormal cell proliferation. In humans, leukocyte telomere length (LTL) progressively shortens with age and is frequently reported to be relatively shorter in aging-related diseases:such as Alzheimer’s disease and vascular dementia. Multiple genetic and non-genetic factors are considered to influence LTL. Over six GWAS have identified several SNPs associated with LTL. Among these, only the TERC locus has been identified and replicated in multiple independent populations for its association with telomere length. However, most published GWAS mainly focus on the populations of European ancestry and no GWAS has been reported in the Chinese population.We performed genome-wide association studies of mean LTL in 2632 individuals using the Affymetrix Genome-Wide Human SNP Array 6.0, with a two-stage replication in 3917 individuals from Chinese populations. To further validate our findings, we get the results of 696 samples from a cohort of European ancestry. We identified two loci associated with LTL that map in telomerase reverse transcriptase (TERT; rs2736100, P= 1.93×10-5) on chromosome 5p15.33 and near keratin 80 (KRT80; rsl7653722, P=6.96 × 10-6) on 12q13.13.SNP rs2736100 is located in intron 2 of TERT, which encodes telomerase reverse transcriptase, played a crucial role in protection of telomere integrity. On 12q13.13, rs17653722 is located 2 kb downstream of KRT80, encoding keratin 80. In Chinese population each C allele of rs2736100 and T allele of rsl7653722 was associated with a longer mean telomere length of 0.026 and 0.059 T/S, respectively, equivalent to about 3 and 7 years of average age-related telomere attrition. Our findings provide new insights into telomere regulatory mechanism and even pathogenesis of age-related diseases.Part 2 Association Analysis of Four Single Nucleotide Polymorphisms with Leukocyte Telomere Length in Two Chinese PopulationsLeukocyte telomere length (LTL) is a predictor of aging and a number of age-related diseases. Recently, four SNPs, rs2630578 in the Bicaudal-D homolog 1 gene (BICD1), rs2162440 and rs7235755 on chromosome 18q12.2, and rs4387287 in the region of the oligonucleotide/oligosaccharide-binding folds containing one gene (OBFC1) have been reported to be associated with LTL. To evaluate the effects of the above SNPs in the populations of mainland China, we conducted an association study of LTL and 4 SNPs of rs2630578, rs2162440, rs7235755 and rs3850673 which is in strong LD with rs4387287(r2=0.898) in two Chinese Han populations.Cohort 1 and cohort 2 were recruited from Shanghai, which were designed for case-control studies of type 2 diabetes. These two cohorts included 4016 individuals and 2533 individuals, ranging from 18 to 96 and 20 to 106 years of age, respectively. LTL was measured by quantitative PCR. Both cohorts showed the expected age-related decline in telomere length (r2=0.055, P<2.2×10-16; r2=0.051, P <2.2×10-16). Telomere length declined by 0.008 T/S per year (r2= 0.055, P<10-16) in cohort 1 and 0.006 T/S per year(r2=0.051, P<10-16) in cohort 2. All SNPs were genotyped and they were found to be in Hardy-Weinberg equilibrium in both cohorts. We found no associations between LTL and four SNPs from BICD1,18q12.2 or OBFC1 adjusted for age, gender and diabetes status.Our results suggest that these SNPs are unlikely to exert a similar effect on LTL in Chinese populations.Part3 Telomere Length in Peripheral Blood Leukocytes and Lung Cancer Risk:A Case-Control Study in Chinese PopulationTelomeres are structures at the ends of eukaryotic chromosomes. Telomere dysfunction is a crucial event in malignant transformation and tumorigenesis. Telomere length in peripheral blood leukocytes has been associated with lung cancer risk, but the relationship has remained controversial. A previous study found that the effect of short leukocyte LTLs on the risk of lung cancer was more pronounced in squamous cell carcinoma than in adenocarcinoma patients, suggesting a histology-specific association of telomere length with lung cancer risk. In this study, we investigated the association of telomere length and the risk of adenocarcinomain Chinese Population.We measured relative telomere lengths in patients in a retrospective case-control study of adenocarcinoma. Logistic regression analysis was performed to evaluate the association between LTL and adenocarcinoma, adjusted for age,gender and smoking status.When the median of telomerelength was used as the cutoff between long and short telomeres, individuals with long telomeres were at a significantly higher risk of lung cancer than those with short telomeres (adjusted odds ratio=3.15,95% confidence interval=2.12-4.67, P<0.0001).Our research demonstrates association between shorter LTL and adenocarcinoma in a population from mainland China. Our results extend the concept that telomere length affects risk of lung cancer in a manner that differs with histological subtype.