基于肌酐估算肾小球滤过率的遗传风险评分评估及其与肾脏结局的关系。

Evaluation of a genetic risk score based on creatinine-estimated glomerular filtration rate and its association with kidney outcomes.

机构信息

Department of Epidemiology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.

Department of Cardiology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.

出版信息

Nephrol Dial Transplant. 2018 Oct 1;33(10):1757-1764. doi: 10.1093/ndt/gfx337.

DOI:10.1093/ndt/gfx337

PMID:29294079

Abstract

BACKGROUND

Meta-analysis of cross-sectional genome-wide association studies (GWAS) on creatinine-estimated glomerular filtration rate (eGFRcrea) identified 53 single-nucleotide polymorphisms (SNPs). These SNP effects can be aggregated into a genetic risk score (GRS) for chronic kidney disease (CKD). To assess its clinical utility, we examined associations with creatinine-estimated kidney outcomes, both cross-sectionally and longitudinally. Additionally, we examined associations with cystatin C-estimated kidney outcomes to verify that a GRS based on eGFRcrea SNPs represents the genetics underlying kidney function.

METHODS

In the community-based Prevention of REnal and Vascular ENdstage Disease (PREVEND) study, we assessed eGFRcrea and eGFRcysc at baseline and four follow-up examinations. The GRS comprised 53 SNPs for eGFRcrea weighted for reported effect-sizes. We adjusted for baseline demographics and renal risk factors.

RESULTS

We included 3649 subjects (median age 49 years, 52% male, median follow-up 11 years, n = 85 baseline CKD, n = 154 incident CKD). At baseline, a higher GRS associated with lower eGFRcrea {adjusted B [95% confidence interval (CI)] = -2.05 (-2.45 to - 1.65) mL/min/1.73 m2, P < 0.001} and higher CKD prevalence [adjusted odds ratio (95% CI) = 1.41 (1.12-1.77), P = 0.002]. During follow-up, a higher GRS associated with higher CKD incidence [adjusted hazard ratio (95% CI) = 1.28 (1.09-1.50), P = 0.004], but no longer significantly after adjustment for baseline eGFR. No significant association with eGFRcrea decline was found. Associations with cystatin C-estimated outcomes were similar.

CONCLUSIONS

The GRS robustly associated with baseline CKD and eGFR, independent of known risk factors. Associations with incident CKD were likely due to low baseline eGFR, not accelerated eGFR decline. The GRS for eGFRcrea likely represents the genetics underlying kidney function, not creatinine metabolism or underlying aetiologies. To improve the clinical utility of GWAS results for CKD, these need to specifically address eGFR decline and CKD incidence.

摘要

背景

对肌氨酸酐估计肾小球滤过率 (eGFRcrea) 的横断面全基因组关联研究 (GWAS) 的荟萃分析确定了 53 个单核苷酸多态性 (SNP)。这些 SNP 效应可以被聚合为慢性肾脏病 (CKD) 的遗传风险评分 (GRS)。为了评估其临床实用性，我们同时从横断面和纵向角度研究了与肌氨酸酐估计的肾脏结局的关联。此外，我们还研究了与胱抑素 C 估计的肾脏结局的关联，以验证基于 eGFRcrea SNPs 的 GRS 代表了肾脏功能的遗传基础。

方法

在基于社区的预防肾脏和血管终末期疾病 (PREVEND) 研究中，我们在基线和四次随访检查中评估了 eGFRcrea 和 eGFRcysc。GRS 由 53 个用于报告效应大小的 SNP 组成，加权为 eGFRcrea。我们调整了基线人口统计学和肾脏危险因素。

结果

我们纳入了 3649 名受试者（中位年龄 49 岁，52%为男性，中位随访时间为 11 年，n=85 名基线 CKD，n=154 名新发 CKD）。在基线时，较高的 GRS 与较低的 eGFRcrea 相关 {调整后的 B [95%置信区间 (CI)]=−2.05（−2.45 至−1.65）mL/min/1.73 m2，P<0.001} 和更高的 CKD 患病率 [调整后的优势比 (95%CI)=1.41（1.12-1.77），P=0.002]。在随访期间，较高的 GRS 与 CKD 发病率较高相关 [调整后的危险比 (95%CI)=1.28（1.09-1.50），P=0.004]，但在调整基线 eGFR 后不再显著。未发现与 eGFRcrea 下降相关的显著关联。与胱抑素 C 估计结果的关联相似。

结论

GRS 与基线 CKD 和 eGFR 显著相关，独立于已知的危险因素。与新发 CKD 的关联可能是由于基线 eGFR 较低，而不是 eGFR 下降加速。基于 eGFRcrea 的 GRS 可能代表了肾脏功能的遗传基础，而不是肌氨酸酐代谢或潜在的病因。为了提高 GWAS 结果在 CKD 中的临床实用性，这些结果需要专门针对 eGFR 下降和 CKD 发病率进行研究。