Telomere length (TL) plays a central role in maintaining cellular proliferative potential and genome stability, leading many investigators to hypothesize that telomere shortening over the life course is a critical mechanism underlying many age-related health conditions. In epidemiological and clinical studies, individuals with relatively short telomeres in peripheral blood cells are often observed to be at increased risk for a wide array of diseases, including cardiovascular conditions, dementia, and multiple types of cancer. However, these associations are difficult to interpret, in part because it is not clear how well TL in peripheral blood cells reflects TL in the tissues most relevant to disease;no studies have addressed this issue in a comprehensive fashion. Furthermore, it is unclear if tissue-specific TL actually reflects levels of genomic instability and DNA damage measured in the same tissue. In this proposal, our first aim is to address this knowledge gap by assessing the correlation between TL measured in whole blood and TL measured in various cancer-prone tissues (breast, colon, esophagus, kidney, lung, ovary, pancreas, prostate, skin, stomach, testis, and vagina) obtained from individuals who have donated tissues to the Genotype-Tissue Expression (GTEx) project. Approximately 100 individuals will be used for each comparison. We will generate data on average TL using a high-throughput, probe-based method that has superior performance compared to traditional PCR-based methods.
Our second aim i s to determine if tissue-specific TL is an indicator for chromosomal instability. To achieve this aim, we will generate data on somatic copy number variation (CNV) and copy-neutral loss of heterozygosity (LOH) events for each tissue type and assess the association between tissue-specific TL and abundance of somatic CNV and LOH events in the same tissue, using approximately 100 individuals for each analysis. CNV and LOH data will be generated using both probe intensity data and allele frequency data derived from high-density SNP arrays that will be run for DNA samples from each tissue. Finally, using existing data on single nucleotide polymorphisms (SNPs) at telomere maintenance gene loci known to effect leukocyte TL and/or cancer risk, we will search for evidence that these variants influence TL in a tissue-specific fashion. Addressing these knowledge gaps regarding correlations among tissue-specific TLs, the relationship between TL and chromosomal instability, and tissue-specific genetic effects on TL is a critical step towards elucidating the role of TL in the etiology of cancer and other common diseases. Our results will provide a foundation for the interpretation of findings from epidemiological studies of leukocyte TL and help guide the design of future studies aimed at elucidating the biological mechanisms and causal pathways linking telomere length and disease, with the long-term goal of using this knowledge to improving health and prevent disease.
Telomere length is has been hypothesized to play a critical role in susceptibility to common diseases, including cancer, with telomere length in blood cells showing associations with disease risk and overall mortality in multiple cohorts. However, these associations are difficult to interpret, in part because it is not clear (1) how well telomere lengh in peripheral blood cells reflects telomere length in the tissues most relevant to disease and (2) if tissue-specific telomere length actually reflects levels of within-tissue chromosomal instabilit. To address these gaps, we propose to assess the cross-tissue correlations among telomere length measurements taken across many cancer-prone tissues and determine if these measures are correlated with chromosomal instability as measured by chromosomal alterations detected within the tissue samples.
|Pierce, Brandon L; Kraft, Peter; Zhang, Chenan (2018) Mendelian randomization studies of cancer risk: a literature review. Curr Epidemiol Rep 5:184-196|
|Jasmine, Farzana; Shinkle, Justin; Sabarinathan, Mekala et al. (2018) A novel pooled-sample multiplex luminex assay for high-throughput measurement of relative telomere length. Am J Hum Biol 30:e23118|
|Delgado, Dayana A; Zhang, Chenan; Chen, Lin S et al. (2018) Genome-wide association study of telomere length among South Asians identifies a second RTEL1 association signal. J Med Genet 55:64-71|
|Dean, Samantha G; Zhang, Chenan; Gao, Jianjun et al. (2017) The association between telomere length and mortality in Bangladesh. Aging (Albany NY) 9:1537-1551|
|eGTEx Project (2017) Enhancing GTEx by bridging the gaps between genotype, gene expression, and disease. Nat Genet 49:1664-1670|
|Yang, Fan; Wang, Jiebiao; GTEx Consortium et al. (2017) Identifying cis-mediators for trans-eQTLs across many human tissues using genomic mediation analysis. Genome Res 27:1859-1871|
|Wang, Jiebiao; Gamazon, Eric R; Pierce, Brandon L et al. (2016) Imputing Gene Expression in Uncollected Tissues Within and Beyond GTEx. Am J Hum Genet 98:697-708|
|Pierce, Brandon L; Jasmine, Farzana; Roy, Shantanu et al. (2016) Telomere length measurement by a novel Luminex-based assay: a blinded comparison to Southern blot. Int J Mol Epidemiol Genet 7:18-23|
|Zhang, Chenan; Lauderdale, Diane S; Pierce, Brandon L (2016) Sex-Specific and Time-Varying Associations Between Cigarette Smoking and Telomere Length Among Older Adults. Am J Epidemiol 184:922-932|
|Kibriya, Muhammad G; Jasmine, Farzana; Roy, Shantanu et al. (2016) Novel Luminex Assay for Telomere Repeat Mass Does Not Show Well Position Effects Like qPCR. PLoS One 11:e0155548|
Showing the most recent 10 out of 11 publications