Background Metabolite levels reflect physiologic homeostasis and may serve as biomarkers of disease progression. Identifying metabolites associated with APOL1 risk alleles—genetic variants associated with CKD risk commonly present in persons of African descent—may reveal novel markers of CKD progression relevant to other populations.

Methods We evaluated associations between the number of APOL1 risk alleles and 760 serum metabolites identified via untargeted profiling in participants of the African American Study of Kidney Disease and Hypertension (AASK) (n=588; Bonferroni significance threshold P<6.5×10⁻⁵) and replicated findings in 678 black participants with CKD in BioMe, an electronic medical record–linked biobank. We tested the metabolite association with CKD progression in AASK, BioMe, and the Modification of Diet in Renal Disease (MDRD) Study.

Results One metabolite, 6-bromotryptophan, was significant in AASK (P=4.7×10⁻⁵) and replicated in BioMe (P=5.7×10⁻³) participants, with lower levels associated with more APOL1 risk alleles. Lower levels of 6-bromotryptophan were associated with CKD progression in AASK and BioMe participants and in white participants in the MDRD Study, independent of demographics and clinical characteristics, including baseline GFR (adjusted hazard ratio per two-fold higher 6-bromotryptophan level, AASK, 0.76; 95% confidence interval [95% CI], 0.64 to 0.91; BioMe, 0.61; 95% CI, 0.43 to 0.85; MDRD, 0.52; 95% CI, 0.34 to 0.79). The interaction between the APOL1 risk alleles and 6-bromotryptophan was not significant. The identity of 6-bromotryptophan was confirmed in experiments comparing its molecular signature with that of authentic standards of other bromotryptophan isomers.

Conclusions Serum 6-bromotryptophan is a consistent and novel risk factor for CKD progression.

背景代谢物水平反映了生理动态平衡，可作为疾病进展的生物标志物。鉴定与APOL1风险等位基因相关的代谢物-非洲人后裔中常见的与CKD风险相关的遗传变异-可能揭示与其他人群相关的CKD进展的新标记。

方法我们的数量之间的关联进行评价APOL1风险等位基因，鉴定760种血清代谢产物经由非靶向分析在肾病和高血压（AASK）的非洲裔美国人研究的参与者（Ñ = 588;邦费罗尼显着阈值P <6.5×10 ^-5）并在电子病历相关的生物库Bio Me中，对678名CKD黑人参与者的研究结果进行了复制。我们在AASK，Bio Me和肾脏疾病饮食（MDRD）研究中测试了代谢物与CKD进展的关系。

结果一种代谢物，6-溴色氨酸，在AASK中显着（P = 4.7×10 ^-5），并在Bio Me（P = 5.7×10 ^-3）参与者中复制，水平较低与更多的APOL1风险等位基因相关。AASK和Bio Me参与者以及MDRD研究中的白人参与者的CKD病情恶化与6-溴色氨酸水平降低有关，而与人口统计学和临床​​特征无关，包括基线GFR（6-溴色氨酸水平提高两倍的调整后的危险比， AASK，0.76； 95％置信区间[95％CI]，0.64至0.91； Bio Me，0.61；95％CI，0.43至0.85；MDRD：0.52；95％CI，0.34至0.79）。APOL1风险等位基因与6-溴色氨酸之间的相互作用不显着。通过将6-溴色氨酸的分子特征与其他溴色氨酸异构体的真实标准物的分子特征进行比较，实验证实了6-溴色氨酸的身份。

结论血清6-溴色氨酸是CKD进展的一致且新颖的危险因素。