The citrate transporter SLC13A5 as a therapeutic target for kidney disease: evidence from Mendelian randomization to inform drug development
Abstract Background Solute carrier family 13 member 5 (SLC13A5) is a Na+-coupled citrate co-transporter that mediates entry of extracellular citrate into the cytosol. SLC13A5 inhibition has been proposed as a target for reducing progression of kidney disease. The aim of this study was to leverage th...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-12-01
|
| Series: | BMC Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12916-023-03227-5 |
| _version_ | 1797376945826037760 |
|---|---|
| author | Dipender Gill Loukas Zagkos Rubinder Gill Thomas Benzing Jens Jordan Andreas L. Birkenfeld Stephen Burgess Grit Zahn |
| author_facet | Dipender Gill Loukas Zagkos Rubinder Gill Thomas Benzing Jens Jordan Andreas L. Birkenfeld Stephen Burgess Grit Zahn |
| author_sort | Dipender Gill |
| collection | DOAJ |
| description | Abstract Background Solute carrier family 13 member 5 (SLC13A5) is a Na+-coupled citrate co-transporter that mediates entry of extracellular citrate into the cytosol. SLC13A5 inhibition has been proposed as a target for reducing progression of kidney disease. The aim of this study was to leverage the Mendelian randomization paradigm to gain insight into the effects of SLC13A5 inhibition in humans, towards prioritizing and informing clinical development efforts. Methods The primary Mendelian randomization analyses investigated the effect of SLC13A5 inhibition on measures of kidney function, including creatinine and cystatin C-based measures of estimated glomerular filtration rate (creatinine-eGFR and cystatin C-eGFR), blood urea nitrogen (BUN), urine albumin-creatinine ratio (uACR), and risk of chronic kidney disease and microalbuminuria. Secondary analyses included a paired plasma and urine metabolome-wide association study, investigation of secondary traits related to SLC13A5 biology, a phenome-wide association study (PheWAS), and a proteome-wide association study. All analyses were compared to the effect of genetically predicted plasma citrate levels using variants selected from across the genome, and statistical sensitivity analyses robust to the inclusion of pleiotropic variants were also performed. Data were obtained from large-scale genetic consortia and biobanks, with sample sizes ranging from 5023 to 1,320,016 individuals. Results We found evidence of associations between genetically proxied SLC13A5 inhibition and higher creatinine-eGFR (p = 0.002), cystatin C-eGFR (p = 0.005), and lower BUN (p = 3 × 10−4). Statistical sensitivity analyses robust to the inclusion of pleiotropic variants suggested that these effects may be a consequence of higher plasma citrate levels. There was no strong evidence of associations of genetically proxied SLC13A5 inhibition with uACR or risk of CKD or microalbuminuria. Secondary analyses identified evidence of associations with higher plasma calcium levels (p = 6 × 10−13) and lower fasting glucose (p = 0.02). PheWAS did not identify any safety concerns. Conclusions This Mendelian randomization analysis provides human-centric insight to guide clinical development of an SLC13A5 inhibitor. We identify plasma calcium and citrate as biologically plausible biomarkers of target engagement, and plasma citrate as a potential biomarker of mechanism of action. Our human genetic evidence corroborates evidence from various animal models to support effects of SLC13A5 inhibition on improving kidney function. |
| first_indexed | 2024-03-08T19:46:49Z |
| format | Article |
| id | doaj.art-ed05579c4a774e6680913e20083f3975 |
| institution | Directory Open Access Journal |
| issn | 1741-7015 |
| language | English |
| last_indexed | 2024-03-08T19:46:49Z |
| publishDate | 2023-12-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medicine |
| spelling | doaj.art-ed05579c4a774e6680913e20083f39752023-12-24T12:21:20ZengBMCBMC Medicine1741-70152023-12-0121111210.1186/s12916-023-03227-5The citrate transporter SLC13A5 as a therapeutic target for kidney disease: evidence from Mendelian randomization to inform drug developmentDipender Gill0Loukas Zagkos1Rubinder Gill2Thomas Benzing3Jens Jordan4Andreas L. Birkenfeld5Stephen Burgess6Grit Zahn7Department of Epidemiology and Biostatistics, School of Public Health, Imperial College LondonDepartment of Epidemiology and Biostatistics, School of Public Health, Imperial College LondonPrimula Group LtdDepartment II of Internal Medicine and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Faculty of Medicine and University Hospital CologneInstitute of Aerospace Medicine, German Aerospace Center (DLR)Department of Diabetology Endocrinology and Nephrology, Internal Medicine IV, University Hospital Tübingen, Eberhard Karls University TübingenMedical Research Council Biostatistics Unit at the University of CambridgeEternygen GmbHAbstract Background Solute carrier family 13 member 5 (SLC13A5) is a Na+-coupled citrate co-transporter that mediates entry of extracellular citrate into the cytosol. SLC13A5 inhibition has been proposed as a target for reducing progression of kidney disease. The aim of this study was to leverage the Mendelian randomization paradigm to gain insight into the effects of SLC13A5 inhibition in humans, towards prioritizing and informing clinical development efforts. Methods The primary Mendelian randomization analyses investigated the effect of SLC13A5 inhibition on measures of kidney function, including creatinine and cystatin C-based measures of estimated glomerular filtration rate (creatinine-eGFR and cystatin C-eGFR), blood urea nitrogen (BUN), urine albumin-creatinine ratio (uACR), and risk of chronic kidney disease and microalbuminuria. Secondary analyses included a paired plasma and urine metabolome-wide association study, investigation of secondary traits related to SLC13A5 biology, a phenome-wide association study (PheWAS), and a proteome-wide association study. All analyses were compared to the effect of genetically predicted plasma citrate levels using variants selected from across the genome, and statistical sensitivity analyses robust to the inclusion of pleiotropic variants were also performed. Data were obtained from large-scale genetic consortia and biobanks, with sample sizes ranging from 5023 to 1,320,016 individuals. Results We found evidence of associations between genetically proxied SLC13A5 inhibition and higher creatinine-eGFR (p = 0.002), cystatin C-eGFR (p = 0.005), and lower BUN (p = 3 × 10−4). Statistical sensitivity analyses robust to the inclusion of pleiotropic variants suggested that these effects may be a consequence of higher plasma citrate levels. There was no strong evidence of associations of genetically proxied SLC13A5 inhibition with uACR or risk of CKD or microalbuminuria. Secondary analyses identified evidence of associations with higher plasma calcium levels (p = 6 × 10−13) and lower fasting glucose (p = 0.02). PheWAS did not identify any safety concerns. Conclusions This Mendelian randomization analysis provides human-centric insight to guide clinical development of an SLC13A5 inhibitor. We identify plasma calcium and citrate as biologically plausible biomarkers of target engagement, and plasma citrate as a potential biomarker of mechanism of action. Our human genetic evidence corroborates evidence from various animal models to support effects of SLC13A5 inhibition on improving kidney function.https://doi.org/10.1186/s12916-023-03227-5SLC13A5CitrateKidneyRenal functionMendelian randomizationDrug development |
| spellingShingle | Dipender Gill Loukas Zagkos Rubinder Gill Thomas Benzing Jens Jordan Andreas L. Birkenfeld Stephen Burgess Grit Zahn The citrate transporter SLC13A5 as a therapeutic target for kidney disease: evidence from Mendelian randomization to inform drug development BMC Medicine SLC13A5 Citrate Kidney Renal function Mendelian randomization Drug development |
| title | The citrate transporter SLC13A5 as a therapeutic target for kidney disease: evidence from Mendelian randomization to inform drug development |
| title_full | The citrate transporter SLC13A5 as a therapeutic target for kidney disease: evidence from Mendelian randomization to inform drug development |
| title_fullStr | The citrate transporter SLC13A5 as a therapeutic target for kidney disease: evidence from Mendelian randomization to inform drug development |
| title_full_unstemmed | The citrate transporter SLC13A5 as a therapeutic target for kidney disease: evidence from Mendelian randomization to inform drug development |
| title_short | The citrate transporter SLC13A5 as a therapeutic target for kidney disease: evidence from Mendelian randomization to inform drug development |
| title_sort | citrate transporter slc13a5 as a therapeutic target for kidney disease evidence from mendelian randomization to inform drug development |
| topic | SLC13A5 Citrate Kidney Renal function Mendelian randomization Drug development |
| url | https://doi.org/10.1186/s12916-023-03227-5 |
| work_keys_str_mv | AT dipendergill thecitratetransporterslc13a5asatherapeutictargetforkidneydiseaseevidencefrommendelianrandomizationtoinformdrugdevelopment AT loukaszagkos thecitratetransporterslc13a5asatherapeutictargetforkidneydiseaseevidencefrommendelianrandomizationtoinformdrugdevelopment AT rubindergill thecitratetransporterslc13a5asatherapeutictargetforkidneydiseaseevidencefrommendelianrandomizationtoinformdrugdevelopment AT thomasbenzing thecitratetransporterslc13a5asatherapeutictargetforkidneydiseaseevidencefrommendelianrandomizationtoinformdrugdevelopment AT jensjordan thecitratetransporterslc13a5asatherapeutictargetforkidneydiseaseevidencefrommendelianrandomizationtoinformdrugdevelopment AT andreaslbirkenfeld thecitratetransporterslc13a5asatherapeutictargetforkidneydiseaseevidencefrommendelianrandomizationtoinformdrugdevelopment AT stephenburgess thecitratetransporterslc13a5asatherapeutictargetforkidneydiseaseevidencefrommendelianrandomizationtoinformdrugdevelopment AT gritzahn thecitratetransporterslc13a5asatherapeutictargetforkidneydiseaseevidencefrommendelianrandomizationtoinformdrugdevelopment AT dipendergill citratetransporterslc13a5asatherapeutictargetforkidneydiseaseevidencefrommendelianrandomizationtoinformdrugdevelopment AT loukaszagkos citratetransporterslc13a5asatherapeutictargetforkidneydiseaseevidencefrommendelianrandomizationtoinformdrugdevelopment AT rubindergill citratetransporterslc13a5asatherapeutictargetforkidneydiseaseevidencefrommendelianrandomizationtoinformdrugdevelopment AT thomasbenzing citratetransporterslc13a5asatherapeutictargetforkidneydiseaseevidencefrommendelianrandomizationtoinformdrugdevelopment AT jensjordan citratetransporterslc13a5asatherapeutictargetforkidneydiseaseevidencefrommendelianrandomizationtoinformdrugdevelopment AT andreaslbirkenfeld citratetransporterslc13a5asatherapeutictargetforkidneydiseaseevidencefrommendelianrandomizationtoinformdrugdevelopment AT stephenburgess citratetransporterslc13a5asatherapeutictargetforkidneydiseaseevidencefrommendelianrandomizationtoinformdrugdevelopment AT gritzahn citratetransporterslc13a5asatherapeutictargetforkidneydiseaseevidencefrommendelianrandomizationtoinformdrugdevelopment |