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 Davila; Patrick Tan; Jing Xian Teo; Khung Keong Yeo; Yiamunaa M; 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

doi:10.1038/s42003-021-02056-7

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 Davila, Patrick Tan, Jing Xian Teo, Khung Keong Yeo, Yiamunaa M, Sylvia Liu, Su Chi Lim, Jianjun Liu, Rob M. van DamYechiel Friedlander, Woon Puay Koh, Jian Min Yuan, Chiea Chuen Khor, Chew Kiat Heng, Rajkumar Dorajoo

Genomics Center

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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.

Original language	English (US)
Article number	519
Journal	Communications biology
Volume	4
Issue number	1
DOIs	https://doi.org/10.1038/s42003-021-02056-7
State	Published - Dec 2021

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© 2021, The Author(s).

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Chang, X., Gurung, R. L., Wang, L., Jin, A., Li, Z., Wang, R., Beckman, K. B., Adams-Haduch, J., Meah, W. Y., Sim, K. S., Lim, W. K., Davila, S., Tan, P., Teo, J. X., Yeo, K. K., M, Y., Liu, S., Lim, S. C., Liu, J., ... Dorajoo, R. (2021). Low frequency variants associated with leukocyte telomere length in the Singapore Chinese population. Communications biology, 4(1), Article 519. https://doi.org/10.1038/s42003-021-02056-7

Chang, X, Gurung, RL, Wang, L, Jin, A, Li, Z, Wang, R, Beckman, KB, Adams-Haduch, J, Meah, WY, Sim, KS, Lim, WK, Davila, S, Tan, P, Teo, JX, Yeo, KK, M, Y, Liu, S, Lim, SC, Liu, J, van Dam, RM, Friedlander, Y, Koh, WP, Yuan, JM, Khor, CC, Heng, CK & Dorajoo, R 2021, 'Low frequency variants associated with leukocyte telomere length in the Singapore Chinese population', Communications biology, vol. 4, no. 1, 519. https://doi.org/10.1038/s42003-021-02056-7

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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.",

author = "Xuling Chang and Gurung, {Resham L.} and Ling Wang and Aizhen Jin and Zheng Li and Renwei Wang and Beckman, {Kenneth B.} and Jennifer Adams-Haduch and Meah, {Wee Yang} and Sim, {Kar Seng} and Lim, {Weng Khong} and Sonia Davila and Patrick Tan and Teo, {Jing Xian} and Yeo, {Khung Keong} and Yiamunaa M and Sylvia Liu and Lim, {Su Chi} and Jianjun Liu and {van Dam}, {Rob M.} and Yechiel Friedlander and Koh, {Woon Puay} and Yuan, {Jian Min} and Khor, {Chiea Chuen} and Heng, {Chew Kiat} and Rajkumar Dorajoo",

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doi = "10.1038/s42003-021-02056-7",

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AU - Chang, Xuling

AU - Gurung, Resham L.

AU - Wang, Ling

AU - Jin, Aizhen

AU - Li, Zheng

AU - Wang, Renwei

AU - Beckman, Kenneth B.

AU - Adams-Haduch, Jennifer

AU - Meah, Wee Yang

AU - Sim, Kar Seng

AU - Lim, Weng Khong

AU - Davila, Sonia

AU - Tan, Patrick

AU - Teo, Jing Xian

AU - Yeo, Khung Keong

AU - M, Yiamunaa

AU - Liu, Sylvia

AU - Lim, Su Chi

AU - Liu, Jianjun

AU - van Dam, Rob M.

AU - Friedlander, Yechiel

AU - Koh, Woon Puay

AU - Yuan, Jian Min

AU - Khor, Chiea Chuen

AU - Heng, Chew Kiat

AU - Dorajoo, Rajkumar

PY - 2021/12

Y1 - 2021/12

N2 - 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.

AB - 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.

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Low frequency variants associated with leukocyte telomere length in the Singapore Chinese population

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