Fang Yu-Wei, Huang Wei-Chung, Wang Chikang, Lin Chien-Yu
Division of Nephrology, Department of Internal Medicine, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei 111, Taiwan.
School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan.
Life (Basel). 2024 Dec 27;15(1):13. doi: 10.3390/life15010013.
Serum cystatin C is a well-established marker of renal function and a valuable predictor of health risks and mortality. DNA methylation-predicted cystatin C (DNAmCystatinC), an advanced epigenetic biomarker, serves as a proxy for serum cystatin C levels. However, the relationships between serum cystatin C, DNAmCystatinC, renal function, and mortality outcomes have not been previously examined. This study aimed to examine the associations between serum cystatin C, DNAmCystatinC, renal function, and their joint and independent relationships with mortality in U.S. adults. We analyzed data from 1642 participants aged 50 and older from the National Health and Nutrition Examination Survey (NHANES) 1999-2002, linked to mortality information from the National Center for Health Statistics (NCHS), with follow-up through 2019. Our analysis demonstrated a positive association between ln-DNAmCystatinC and ln-serum cystatin C (Adjusted β (SE) = 0.773 (0.267), = 0.007), while ln-DNAmCystatinC was negatively correlated with ln-Estimated glomerular filtration rate, calculated using both creatinine and cystatin C (eGFRcr-cys) (Adjusted β (SE) = -1.123 (0.449), = 0.018). In a weighted Cox regression model, a one-unit increase in ln-serum cystatin C was linked to an increased hazard ratio (HR) of 2.87 (95% CI: 1.938-4.26, < 0.001) for all-cause mortality and 3.04 (95% CI: 1.34-6.88, = 0.010) for cardiovascular mortality. Additionally, a one-unit increase in ln-DNAmCystatinC was associated with an HR of 135.86 (95% CI: 5.51-3349.69, = 0.004) for all-cause mortality. This association was particularly pronounced in participants without chronic kidney disease (CKD), with a -value for the interaction between DNAmCystatinC and CKD on all-cause mortality of 0.002. Furthermore, individuals with serum cystatin C and DNAmCystatinC levels above the 50th percentile showed the highest all-cause mortality risk when compared to other subgroups. In conclusion, our findings demonstrate that DNAmCystatinC is a stronger predictor of all-cause mortality than serum cystatin C, with potential additive effects when both biomarkers are considered together. These results suggest their utility as valuable clinical indicators for risk stratification and early intervention. Future research should validate these findings and further explore the clinical and public health implications of epigenetic biomarkers.
血清胱抑素C是一种公认的肾功能标志物，也是健康风险和死亡率的重要预测指标。DNA甲基化预测的胱抑素C（DNAm胱抑素C）是一种先进的表观遗传生物标志物，可作为血清胱抑素C水平的替代指标。然而，血清胱抑素C、DNAm胱抑素C、肾功能和死亡率结局之间的关系此前尚未得到研究。本研究旨在探讨美国成年人血清胱抑素C、DNAm胱抑素C、肾功能及其与死亡率的联合和独立关系。我们分析了1999 - 2002年美国国家健康与营养检查调查（NHANES）中1642名50岁及以上参与者的数据，并与国家卫生统计中心（NCHS）的死亡率信息相关联，随访至2019年。我们的分析表明，ln-DNAm胱抑素C与ln-血清胱抑素C之间呈正相关（调整后的β（标准误）= 0.773（0.267），P = 0.007），而ln-DNAm胱抑素C与使用肌酐和胱抑素C计算的ln-估计肾小球滤过率（eGFRcr-cys）呈负相关（调整后的β（标准误）= -1.123（0.449），P = 0.018）。在加权Cox回归模型中，ln-血清胱抑素C每增加一个单位，全因死亡率的风险比（HR）增加2.87（95%可信区间：1.938 - 4.26，P < 0.001），心血管死亡率的HR增加3.04（95%可信区间：1.34 - 6.88，P = 0.010）。此外，ln-DNAm胱抑素C每增加一个单位，全因死亡率的HR为135.86（95%可信区间：5.51 - 3349.69，P = 0.004）。这种关联在无慢性肾脏病（CKD）的参与者中尤为明显，DNAm胱抑素C与CKD对全因死亡率的交互作用P值为0.002。此外，与其他亚组相比，血清胱抑素C和DNAm胱抑素C水平高于第50百分位数的个体全因死亡风险最高。总之，我们的研究结果表明，DNAm胱抑素C比血清胱抑素C是全因死亡率更强的预测指标，当同时考虑这两种生物标志物时可能具有相加效应。这些结果表明它们作为风险分层和早期干预的有价值临床指标的实用性。未来的研究应验证这些发现，并进一步探索表观遗传生物标志物的临床和公共卫生意义。
