Genetic studies of paired metabolomes reveal enzymatic and transport processes at the interface of plasma and urine

被引：32

作者：

Schlosser, Pascal ^{[1
,2
,3
]}

Scherer, Nora ^{[1
,2
,4
]}

Grundner-Culemann, Franziska ^{[1
,2
]}

Monteiro-Martins, Sara ^{[1
,2
]}

Haug, Stefan ^{[1
,2
]}

Steinbrenner, Inga ^{[1
,2
]}

Uluvar, Burulca ^{[1
,2
]}

Wuttke, Matthias ^{[1
,2
]}

Cheng, Yurong ^{[1
,2
]}

Ekici, Arif B. ^{[5
]}

Gyimesi, Gergely ^{[6
,7
]}

Karoly, Edward D. ^{[8
]}

Kotsis, Fruzsina ^{[2
,9
]}

Mielke, Johanna ^{[10
]}

Gomez, Maria F. ^{[11
]}

Yu, Bing ^{[12
]}

Grams, Morgan E. ^{[13
]}

Coresh, Josef ^{[3
]}

Boerwinkle, Eric ^{[12
,14
]}

Koettgen, Michael ^{[15
]}

Kronenberg, Florian ^{[16
]}

Meiselbach, Heike ^{[17
]}

Mohney, Robert P.

Akilesh, Shreeram ^{[18
]}

Schmidts, Miriam ^{[19
]}

Hediger, Matthias A.

Schultheiss, Ulla T. ^{[1
,2
]}

Eckardt, Kai-Uwe ^{[17
,20
]}

Oefner, Peter J. ^{[21
]}

Sekula, Peggy ^{[1
,2
]}

Li, Yong ^{[1
,2
]}

Koettgen, Anna ^{[1
,2
,3
]}

机构：

[1] Univ Freiburg, Fac Med, Inst Genet Epidemiol, Freiburg, Germany

[2] Univ Freiburg, Med Ctr, Freiburg, Germany

[3] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21218 USA

[4] Univ Freiburg, Spemann Grad Sch Biol & Med, Freiburg, Germany

[5] Friedrich Alexander Univ Erlangen Nurnberg, Univ Hosp Erlangen, Inst Human Genet, Erlangen, Germany

[6] Univ Bern, Dept Hypertens & Nephrol, Membrane Transport Discovery Lab, Bern, Switzerland

[7] Univ Bern, Dept Biomed Res, Bern, Switzerland

[8] Metabolon Inc, Morrisville, NC USA

[9] Univ Freiburg, Fac Med, Dept Med Nephrol & Primary Care 4, Freiburg, Germany

[10] Bayer AG, Res & Early Dev, Div Pharmaceut, Wuppertal, Germany

[11] Lund Univ, Diabet Ctr, Dept Clin Sci Malmo, Lund, Sweden

[12] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Epidemiol Human Genet & Environm Sci, Houston, TX 77030 USA

[13] NYU Grossman Sch Med, New York, NY USA

[14] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA

[15] Albert Ludwigs Univ Freiburg, Ctr Integrat Biol Signalling Studies CIBSS, Freiburg, Germany

[16] Med Univ Innsbruck, Dept Genet, Inst Genet Epidemiol, Innsbruck, Austria

[17] Friedrich Alexander Univ Erlangen Nurnberg, Univ Hosp Erlangen, Dept Nephrol & Hypertens, Erlangen, Germany

[18] Univ Washington, Dept Lab Med & Pathol, Seattle, WA 98195 USA

[19] Freiburg Univ, Univ Hosp Freiburg, Ctr Pediat & Adolescent Med, Fac Med, Freiburg, Germany

[20] Charite Univ Med Berlin, Dept Nephrol & Med Intens Care, Berlin, Germany

[21] Univ Regensburg, Inst Funct Genom, Regensburg, Germany

来源：

NATURE GENETICS | 2023年 / 55卷 / 06期

基金：

美国国家卫生研究院; 欧洲研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; KIDNEY-DISEASE GCKD; GENOTYPE IMPUTATION; RENAL DIPEPTIDASE; VARIANTS; ATLAS; IDENTIFICATION; VISUALIZATION; CHILDREN; ILEAL;

D O I：

10.1038/s41588-023-01409-8

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

The kidneys operate at the interface of plasma and urine by clearing molecular waste products while retaining valuable solutes. Genetic studies of paired plasma and urine metabolomes may identify underlying processes. We conducted genome-wide studies of 1,916 plasma and urine metabolites and detected 1,299 significant associations. Associations with 40% of implicated metabolites would have been missed by studying plasma alone. We detected urine-specific findings that provide information about metabolite reabsorption in the kidney, such as aquaporin (AQP)-7-mediated glycerol transport, and different metabolomic footprints of kidney-expressed proteins in plasma and urine that are consistent with their localization and function, including the transporters NaDC3 (SLC13A3) and ASBT (SLC10A2). Shared genetic determinants of 7,073 metabolite-disease combinations represent a resource to better understand metabolic diseases and revealed connections of dipeptidase 1 with circulating digestive enzymes and with hypertension. Extending genetic studies of the metabolome beyond plasma yields unique insights into processes at the interface of body compartments.

引用

页码：995 / +

页数：32

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