Division of Nephrology and Hypertension, Vanderbilt Center for Kidney Disease, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee.
J Am Soc Nephrol. 2023 Sep 1;34(9):1547-1559. doi: 10.1681/ASN.0000000000000170. Epub 2023 Jun 1.
Rapid progression of CKD is associated with poor clinical outcomes. Most previous studies looking for genetic factors associated with low eGFR have used cross-sectional data. The authors conducted a meta-analysis of genome-wide association studies of eGFR decline among 116,870 participants with CKD, focusing on longitudinal data. They identified three loci (two of them novel) associated with longitudinal eGFR decline. In addition to the known UMOD/PDILT locus, variants within BICC1 were associated with significant differences in longitudinal eGFR slope. Variants within HEATR4 also were associated with differences in eGFR decline, but only among Black/African American individuals without diabetes. These findings help characterize molecular mechanisms of eGFR decline in CKD and may inform new therapeutic approaches for progressive kidney disease.
Rapid progression of CKD is associated with poor clinical outcomes. Despite extensive study of the genetics of cross-sectional eGFR, only a few loci associated with eGFR decline over time have been identified.
We performed a meta-analysis of genome-wide association studies of eGFR decline among 116,870 participants with CKD-defined by two outpatient eGFR measurements of <60 ml/min per 1.73 m 2 , obtained 90-365 days apart-from the Million Veteran Program and Vanderbilt University Medical Center's DNA biobank. The primary outcome was the annualized relative slope in outpatient eGFR. Analyses were stratified by ethnicity and diabetes status and meta-analyzed thereafter.
In cross-ancestry meta-analysis, the strongest association was rs77924615, near UMOD / PDILT ; each copy of the G allele was associated with a 0.30%/yr faster eGFR decline ( P = 4.9×10 -27 ). We also observed an association within BICC1 (rs11592748), where every additional minor allele was associated with a 0.13%/yr slower eGFR decline ( P = 5.6×10 -9 ). Among participants without diabetes, the strongest association was the UMOD/PDILT variant rs36060036, associated with a 0.27%/yr faster eGFR decline per copy of the C allele ( P = 1.9×10 -17 ). Among Black participants, a significantly faster eGFR decline was associated with variant rs16996674 near APOL1 (R 2 =0.29 with the G1 high-risk genotype); among Black participants with diabetes, lead variant rs11624911 near HEATR4 also was associated with a significantly faster eGFR decline. We also nominally replicated loci with known associations with eGFR decline, near PRKAG2, FGF5, and C15ORF54.
Three loci were significantly associated with longitudinal eGFR change at genome-wide significance. These findings help characterize molecular mechanisms of eGFR decline and may contribute to the development of new therapeutic approaches for progressive CKD.
声明：慢性肾脏病（CKD）的快速进展与不良临床结局相关。大多数先前研究寻找与低肾小球滤过率（eGFR）相关的遗传因素时都使用了横断面数据。作者对 116870 例 CKD 患者的 eGFR 下降的全基因组关联研究进行了荟萃分析，重点关注纵向数据。他们确定了与纵向 eGFR 下降相关的三个基因座（其中两个为新发现的）。除了已知的 UMOD/PDILT 基因座外，BICC1 内的变体与纵向 eGFR 斜率的显著差异相关。HEATR4 内的变体也与 eGFR 下降的差异相关，但仅在没有糖尿病的黑人和非裔美国人个体中存在。这些发现有助于描述 CKD 中 eGFR 下降的分子机制，并可能为进展性肾脏疾病提供新的治疗方法。
慢性肾脏病（CKD）的快速进展与不良临床结局相关。尽管对横断面 eGFR 的遗传学进行了广泛研究，但仅确定了少数与随时间推移的 eGFR 下降相关的基因座。
我们对来自百万退伍军人计划和范德比尔特大学医学中心 DNA 生物库的 116870 例 CKD 患者的 eGFR 下降的全基因组关联研究进行了荟萃分析，这些患者的两次门诊 eGFR 测量值均<60ml/min/1.73m 2 ，间隔 90-365 天。主要结局是门诊 eGFR 的年化相对斜率。根据种族和糖尿病状况进行分层分析，然后进行荟萃分析。
在跨种族荟萃分析中，最强的关联是 rs77924615，位于 UMOD/PDILT 附近；每个 G 等位基因的拷贝与 eGFR 下降速度加快 0.30%/年相关（P=4.9×10 -27 ）。我们还在 BICC1 内观察到关联（rs11592748），每个额外的次要等位基因与 eGFR 下降速度减慢 0.13%/年相关（P=5.6×10 -9 ）。在没有糖尿病的参与者中，最强的关联是 UMOD/PDILT 变体 rs36060036，与 C 等位基因每增加一个拷贝 eGFR 下降速度加快 0.27%/年相关（P=1.9×10 -17 ）。在黑人参与者中，APOL1 附近的变体 rs16996674 与 eGFR 下降速度加快显著相关（R 2 =0.29，与高风险 G1 基因型相关）；在黑人糖尿病患者中，HEATR4 附近的主要变体 rs11624911 也与 eGFR 下降速度加快显著相关。我们还在 PRKAG2、FGF5 和 C15ORF54 附近的已知与 eGFR 下降相关的基因座上进行了名义复制。
三个基因座与全基因组显著相关的纵向 eGFR 变化相关。这些发现有助于描述 eGFR 下降的分子机制，并可能有助于开发治疗进展性 CKD 的新方法。
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