Abstract
The role of low frequency variants associated with telomere length homeostasis in chronic diseases and mortalities is relatively understudied in the East-Asian population. Here we evaluated low frequency variants, including 1,915,154 Asian specific variants, for leukocyte telomere length (LTL) associations among 25,533 Singapore Chinese samples. Three East Asian specific variants in/near POT1, TERF1 and STN1 genes are associated with LTL (Meta-analysis P 2.49×10−14–6.94×10−10). Rs79314063, a missense variant (p.Asp410His) at POT1, shows effect 5.3 fold higher and independent of a previous common index SNP. TERF1 (rs79617270) and STN1 (rs139620151) are linked to LTL-associated common index SNPs at these loci. Rs79617270 is associated with cancer mortality [HR95%CI = 1.544 (1.173, 2.032), PAdj = 0.018] and 4.76% of the association between the rs79617270 and colon cancer is mediated through LTL. Overall, genetically determined LTL is particularly associated with lung adenocarcinoma [HR95%CI = 1.123 (1.051, 1.201), Padj = 0.007]. Ethnicity-specific low frequency variants may affect LTL homeostasis and associate with certain cancers.
Highlights
The role of low frequency variants associated with telomere length homeostasis in chronic diseases and mortalities is relatively understudied in the East-Asian population
Asian specific variants in/near POT1, TERF1 and STN1 genes are associated with leukocyte telomere length (LTL) (Metaanalysis P 2.49×10−14–6.94×10−10)
Many POT1 mutants that result in the loss of DNA-binding capacity but retain TPP1 binding may lead to an increase of telomere length in cells that have telomerase activity and correspondingly many rare functional variants in
Summary
The role of low frequency variants associated with telomere length homeostasis in chronic diseases and mortalities is relatively understudied in the East-Asian population. We evaluated low frequency variants, including 1,915,154 Asian specific variants, for leukocyte telomere length (LTL) associations among 25,533 Singapore Chinese samples. Asian specific variants in/near POT1, TERF1 and STN1 genes are associated with LTL (Metaanalysis P 2.49×10−14–6.94×10−10). Ethnicity-specific low frequency variants may affect LTL homeostasis and associate with certain cancers. Children’s Medical Institute, National University Health System, Singapore, Singapore. T elomere length has been associated with risks of cancers, other chronic diseases and mortalities[1,2,3,4]. When telomere length is critically shortened, cells enter a state of growth arrest[6,7]. The enzyme telomerase, which lengthens telomeres and promotes cell proliferation and survival, is activated in most human cancers[3,9]
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