Yansen Bai1, Wenshan Fu1, Xin Guan1, Xiulong Wu1, Guyanan Li1, Wei Wei1, Yue Feng1, Hua Meng1, Hang Li1, Mengying Li1, Ming Fu1, Jiali Jie1, Chenming Wang1, Xiaomin Zhang1, Meian He1, Huan Guo2. 1. Department of Occupational and Environmental Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. 2. Department of Occupational and Environmental Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: ghuan5011@hust.edu.cn.
Abstract
OBJECTIVE: Telomere is required for maintaining chromosome stability and genome integrity, while telomere length is sensitive to environmental stressors. We aimed to identify the effects of multiple metals co-exposure as well as their joint effects with TERT-CLPTM1L variants on leukocyte telomere length (LTL). METHODS: This study included 842 workers from a coke-oven plant, of whom plasma concentrations of 23 metals and LTL were determined. Genetic variations in TERT-CLPTM1L were genotyped by using the Global Screening Array. Multipollutant-based statistical methods, including the Bonferroni-correction, backward elimination procedure, and LASSO penalized regression analysis, were used to select the LTL-associated metals. Generalized linear regression models were used to evaluate the joint effects of TERT-CLPTM1L variants with positive metal on LTL. RESULTS: Each 1% increase in plasma concentration of manganese (Mn) was significantly associated with a 0.153% increase in LTL [β(95%CI) = 0.153(0.075, 0.230), P < 0.001] in single-metal models after Bonferroni-correction. The multiple-metal models and the LASSO penalized regression analysis both indicated Mn as the sole significant predictor for LTL. Furthermore, 5 tagSNPs (rs33954691, rs6554759, rs465498, rs2455393, and rs31489) in TERT-CLPTM1L with high plasma Mn (>4.21 μg/L) showed joint effects on increasing LTL. CONCLUSIONS: Our study revealed the independent and positive association between plasma Mn and LTL when accounting for co-exposure to other metals. This effect can be further enhanced by TERT-CLPTM1L variants. These results may advance our understanding of the complex interplay between genetic and environmental factors on telomere length. Further experimental studies are warranted to elucidate the underlying mechanisms.
OBJECTIVE: Telomere is required for maintaining chromosome stability and genome integrity, while telomere length is sensitive to environmental stressors. We aimed to identify the effects of multiple metals co-exposure as well as their joint effects with TERT-CLPTM1L variants on leukocyte telomere length (LTL). METHODS: This study included 842 workers from a coke-oven plant, of whom plasma concentrations of 23 metals and LTL were determined. Genetic variations in TERT-CLPTM1L were genotyped by using the Global Screening Array. Multipollutant-based statistical methods, including the Bonferroni-correction, backward elimination procedure, and LASSO penalized regression analysis, were used to select the LTL-associated metals. Generalized linear regression models were used to evaluate the joint effects of TERT-CLPTM1L variants with positive metal on LTL. RESULTS: Each 1% increase in plasma concentration of manganese (Mn) was significantly associated with a 0.153% increase in LTL [β(95%CI) = 0.153(0.075, 0.230), P < 0.001] in single-metal models after Bonferroni-correction. The multiple-metal models and the LASSO penalized regression analysis both indicated Mn as the sole significant predictor for LTL. Furthermore, 5 tagSNPs (rs33954691, rs6554759, rs465498, rs2455393, and rs31489) in TERT-CLPTM1L with high plasma Mn (>4.21 μg/L) showed joint effects on increasing LTL. CONCLUSIONS: Our study revealed the independent and positive association between plasma Mn and LTL when accounting for co-exposure to other metals. This effect can be further enhanced by TERT-CLPTM1L variants. These results may advance our understanding of the complex interplay between genetic and environmental factors on telomere length. Further experimental studies are warranted to elucidate the underlying mechanisms.
Authors: Hongjie Chen; Arunabha Majumdar; Lu Wang; Siddhartha Kar; Kevin M Brown; Helian Feng; Constance Turman; Joe Dennis; Douglas Easton; Kyriaki Michailidou; Jacques Simard; Timothy Bishop; Iona C Cheng; Jeroen R Huyghe; Stephanie L Schmit; Tracy A O'Mara; Amanda B Spurdle; Puya Gharahkhani; Johannes Schumacher; Janusz Jankowski; Ines Gockel; Melissa L Bondy; Richard S Houlston; Robert B Jenkins; Beatrice Melin; Corina Lesseur; Andy R Ness; Brenda Diergaarde; Andrew F Olshan; Christopher I Amos; David C Christiani; Maria T Landi; James D McKay; Myriam Brossard; Mark M Iles; Matthew H Law; Stuart MacGregor; Jonathan Beesley; Michelle R Jones; Jonathan Tyrer; Stacey J Winham; Alison P Klein; Gloria Petersen; Donghui Li; Brian M Wolpin; Rosalind A Eeles; Christopher A Haiman; Zsofia Kote-Jarai; Fredrick R Schumacher; Paul Brennan; Stephen J Chanock; Valerie Gaborieau; Mark P Purdue; Paul Pharoah; Rayjean J Hung; Laufey T Amundadottir; Peter Kraft; Bogdan Pasaniuc; Sara Lindström Journal: HGG Adv Date: 2021-06-12