Low frequency variants associated with leukocyte telomere length in the Singapore Chinese population
Xuling Chang, Resham L Gurung, Ling Wang, Aizhen Jin, Zheng Li, Renwei Wang, Kenneth B. Beckman, Jennifer Adams‐Haduch, Wee Yang Meah, Kar Seng Sim, Weng Khong Lim, Sonia Dávila, Patrick Tan, Jing Xian Teo, Khung Keong Yeo, M Yiamunaa, Sylvia Liu, Su Chi Lim, Jianjun Liu, Rob M. van Dam, Yechiel Friedlander, Woon‐Puay Koh, Jian‐Min Yuan, Chiea Chuen Khor, Chew‐Kiat Heng, Rajkumar Dorajoo
Abstract
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 [HR 95%CI = 1.544 (1.173, 2.032), P Adj = 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 [HR 95%CI = 1.123 (1.051, 1.201), P adj = 0.007]. Ethnicity-specific low frequency variants may affect LTL homeostasis and associate with certain cancers.