儿童癌症幸存者的健康相关生活质量和基于 DNA 甲基化的衰老生物标志物。
Health-related quality of life and DNA methylation-based aging biomarkers among survivors of childhood cancer.
机构信息
Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, TN, USA.
Department of Biostatistics, St Jude Children's Research Hospital, Memphis, TN, USA.
出版信息
J Natl Cancer Inst. 2024 Jul 1;116(7):1116-1125. doi: 10.1093/jnci/djae046.
BACKGROUND
Childhood cancer survivors are at high risk for morbidity and mortality and poor patient-reported outcomes, typically health-related quality of life (HRQOL). However, associations between DNA methylation-based aging biomarkers and HRQOL have not been evaluated.
METHODS
DNA methylation was generated with Infinium EPIC BeadChip on blood-derived DNA (median for age at blood draw = 34.5 years, range = 18.5-66.6 years), and HRQOL was assessed with age at survey (mean = 32.3 years, range = 18.4-64.5 years) from 2206 survivors in the St Jude Lifetime Cohort. DNA methylation-based aging biomarkers, including epigenetic age using multiple clocks (eg, GrimAge) and others (eg, DNAmB2M: beta-2-microglobulin; DNAmADM: adrenomedullin), were derived from the DNAm Age Calculator (https://dnamage.genetics.ucla.edu). HRQOL was assessed using the Medical Outcomes Study 36-Item Short-Form Health Survey to capture 8 domains and physical and mental component summaries. General linear models evaluated associations between HRQOL and epigenetic age acceleration (EAA; eg, EAA_GrimAge) or other age-adjusted DNA methylation-based biomarkers (eg, ageadj_DNAmB2M) after adjusting for age at blood draw, sex, cancer treatments, and DNA methylation-based surrogate for smoking pack-years. All P values were 2-sided.
RESULTS
Worse HRQOL was associated with greater EAA_GrimAge (physical component summaries: β = -0.18 years, 95% confidence interval [CI] = -0.251 to -0.11 years; P = 1.85 × 10-5; and 4 individual HRQOL domains), followed by ageadj_DNAmB2M (physical component summaries: β = -0.08 years, 95% CI = -0.124 to -0.037 years; P = .003; and 3 individual HRQOL domains) and ageadj_DNAmADM (physical component summaries: β = -0.082 years, 95% CI = -0.125 to -0.039 years; P = .002; and 2 HRQOL domains). EAA_Hannum (Hannum clock) was not associated with any HRQOL.
CONCLUSIONS
Overall and domain-specific measures of HRQOL are associated with DNA methylation measures of biological aging. Future longitudinal studies should test biological aging as a potential mechanism underlying the association between poor HRQOL and increased risk of clinically assessed adverse health outcomes.
背景
儿童癌症幸存者面临较高的发病率和死亡率，以及较差的患者报告结局，通常是健康相关的生活质量（HRQOL）。然而，基于 DNA 甲基化的衰老生物标志物与 HRQOL 之间的关联尚未得到评估。
方法
使用 Infinium EPIC BeadChip 在血液衍生的 DNA 上生成 DNA 甲基化（采血时年龄中位数=34.5 岁，范围为 18.5-66.6 岁），并使用来自 2206 名圣裘德终身队列幸存者的调查时年龄（平均=32.3 岁，范围为 18.4-64.5 岁）评估 HRQOL。基于 DNA 甲基化的衰老生物标志物，包括使用多个时钟（例如 GrimAge）和其他方法（例如 DNAmB2M：β-2-微球蛋白；DNAmADM：肾上腺髓质素）计算的表观遗传年龄，这些方法均来自于 DNAm Age Calculator（https://dnamage.genetics.ucla.edu）。使用医疗结果研究 36 项简短健康调查评估 HRQOL，以捕获 8 个领域和身体与精神成分综合评分。在调整采血时年龄、性别、癌症治疗以及吸烟包年数的 DNA 甲基化替代指标后，使用一般线性模型评估 HRQOL 与表观遗传年龄加速（EAA；例如，EAA_GrimAge）或其他年龄调整的基于 DNA 甲基化的生物标志物（例如，ageadj_DNAmB2M）之间的关联。所有 P 值均为双侧。
结果
较差的 HRQOL 与更大的 EAA_GrimAge（身体成分综合评分：β=-0.18 岁，95%置信区间[CI]：-0.251 至-0.11 岁；P=1.85×10-5；以及 4 个 HRQOL 单项评分）、ageadj_DNAmB2M（身体成分综合评分：β=-0.08 岁，95%CI：-0.124 至-0.037 岁；P=0.003；以及 3 个 HRQOL 单项评分）和 ageadj_DNAmADM（身体成分综合评分：β=-0.082 岁，95%CI：-0.125 至-0.039 岁；P=0.002；以及 2 个 HRQOL 单项评分）相关。EAA_Hannum（Hannum 时钟）与任何 HRQOL 均无关。
结论
总体和特定领域的 HRQOL 指标与生物衰老的 DNA 甲基化指标相关。未来的纵向研究应该检验生物衰老是否是 HRQOL 较差与临床评估的不良健康结果风险增加之间关联的潜在机制。
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