Epigenome-wide association study of kidney function identifies trans-ethnic and ethnic-specific loci.
Epigenome-wide association study of kidney function identifies trans-ethnic and ethnic-specific loci.
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DOI：
10.1186/s13073-021-00877-z
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发表时间：
2021-04-30
期刊：
影响因子：
12.3
通讯作者：
Franceschini N
中科院分区：
文献类型：
--
作者：
Breeze CE;Batorsky A;Lee MK;Szeto MD;Xu X;McCartney DL;Jiang R;Patki A;Kramer HJ;Eales JM;Raffield L;Lange L;Lange E;Durda P;Liu Y;Tracy RP;Van Den Berg D;NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed MESA Multi-Omics Working Group;Evans KL;Kraus WE;Shah S;Tiwari HK;Hou L;Whitsel EA;Jiang X;Charchar FJ;Baccarelli AA;Rich SS;Morris AP;Irvin MR;Arnett DK;Hauser ER;Rotter JI;Correa A;Hayward C;Horvath S;Marioni RE;Tomaszewski M;Beck S;Berndt SI;London SJ;Mychaleckyj JC;Franceschini N
DNA甲基化（DNAm）与基因调控和估计的肾小球滤过率（eGFR）相关，eGFR是衡量肾功能的指标。eGFR降低在美国西班牙裔和非洲裔美国人中更常见。对此原因知之甚少。我们的目标是使用不可知的全基因组方法来识别与eGFR相关的跨种族和种族特异性差异甲基化位置（DMP）。该研究包括来自多种族研究的5428名参与者和8109名参与者。我们使用来自Illumina 450K或EPIC阵列的β值测试了全血DNAm和eGFR之间的关联。使用线性混合模型进行种族分层分析，调整年龄、性别、吸烟和研究特定和技术变量。对汇总结果进行了种族内和种族间的荟萃分析。结果进行了评估，使用整合表观基因组学方法和途径分析。我们在FDR为0.05时确定了93个与eGFR相关的DMP，并在跨种族和非裔美国人荟萃分析中分别在独立样本中重复了13个和1个DMP。该研究还验证了6个先前发表的DMP。已鉴定的DMPs显示与肾组织中的DNase I超敏位点、与近端基因表达相关的位点以及与肾组织和肾发育相关的转录因子基序和途径显著重叠富集。我们发现了与eGFR相关的跨种族和种族特异性DMP，包括富含肾脏组织中调控元件的DMP和与肾脏发育相关的途径。这些发现揭示了与肾功能相关的表观遗传机制，弥合了群体特异性eGFR相关DNA m和组织特异性调控背景之间的差距。
DNA methylation (DNAm) is associated with gene regulation and estimated glomerular filtration rate (eGFR), a measure of kidney function. Decreased eGFR is more common among US Hispanics and African Americans. The causes for this are poorly understood. We aimed to identify trans-ethnic and ethnic-specific differentially methylated positions (DMPs) associated with eGFR using an agnostic, genome-wide approach. The study included up to 5428 participants from multi-ethnic studies for discovery and 8109 participants for replication. We tested the associations between whole blood DNAm and eGFR using beta values from Illumina 450K or EPIC arrays. Ethnicity-stratified analyses were performed using linear mixed models adjusting for age, sex, smoking, and study-specific and technical variables. Summary results were meta-analyzed within and across ethnicities. Findings were assessed using integrative epigenomics methods and pathway analyses. We identified 93 DMPs associated with eGFR at an FDR of 0.05 and replicated 13 and 1 DMPs across independent samples in trans-ethnic and African American meta-analyses, respectively. The study also validated 6 previously published DMPs. Identified DMPs showed significant overlap enrichment with DNase I hypersensitive sites in kidney tissue, sites associated with the expression of proximal genes, and transcription factor motifs and pathways associated with kidney tissue and kidney development. We uncovered trans-ethnic and ethnic-specific DMPs associated with eGFR, including DMPs enriched in regulatory elements in kidney tissue and pathways related to kidney development. These findings shed light on epigenetic mechanisms associated with kidney function, bridging the gap between population-specific eGFR-associated DNAm and tissue-specific regulatory context.
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影响因子：
4.4
作者：
Bibikova, Marina;Barnes, Bret;Shen, Richard
通讯作者：
Shen, Richard
影响因子：
16.6
作者：
Chu AY;Tin A;Schlosser P;Ko YA;Qiu C;Yao C;Joehanes R;Grams ME;Liang L;Gluck CA;Liu C;Coresh J;Hwang SJ;Levy D;Boerwinkle E;Pankow JS;Yang Q;Fornage M;Fox CS;Susztak K;Köttgen A
通讯作者：
Köttgen A
DOI：
10.1056/nejmoa1114248
发表时间：
2012-07-05
期刊：
The New England journal of medicine
影响因子：
--
作者：
Inker LA;Schmid CH;Tighiouart H;Eckfeldt JH;Feldman HI;Greene T;Kusek JW;Manzi J;Van Lente F;Zhang YL;Coresh J;Levey AS;CKD-EPI Investigators
通讯作者：
CKD-EPI Investigators
影响因子：
5.5
作者：
通讯作者：
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Pax2可能通过调节TBX1的表达在肾脏发育中发挥作用
影响因子：
2.8
作者：
Jiang, Hongkun;Li, Lei;Li, Yunpeng
通讯作者：
Li, Yunpeng