Four missense genetic variants in CUBN are associated with higher levels of eGFR in non-diabetes but not in diabetes mellitus or its subtypes: A genetic association study in Europeans
AimRare genetic variants in the CUBN gene encoding the main albumin-transporter in the proximal tubule of the kidneys have previously been associated with microalbuminuria and higher urine albumin levels, also in diabetes. Sequencing studies in isolated proteinuria suggest that these variants might...
Gespeichert in:
| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
28 February 2023
|
| In: |
Frontiers in endocrinology
Year: 2023, Jahrgang: 14, Pages: 1-11 |
| ISSN: | 1664-2392 |
| DOI: | 10.3389/fendo.2023.1081741 |
| Online-Zugang: | Resolving-System, kostenfrei, Volltext: https://doi.org/10.3389/fendo.2023.1081741 Verlag, kostenfrei, Volltext: https://www.frontiersin.org/articles/10.3389/fendo.2023.1081741 
|
| Verfasserangaben: | Nicoline Uglebjerg, Fariba Ahmadizar, Dina M. Aly, Marisa Cañadas-Garre, Claire Hill, Annemieke Naber, Asmundur Oddsson, Sunny S. Singh, Laura Smyth, David-Alexandre Trégouët, Layal Chaker, Mohsen Ghanbari, Valgerdur Steinthorsdottir, Emma Ahlqvist, Samy Hadjadj, Mandy Van Hoek, Maryam Kavousi, Amy Jayne McKnight, Eric J. Sijbrands, Kari Stefansson, Matias Simons, Peter Rossing and Tarunveer S. Ahluwalia |
MARC
| LEADER | 00000caa a2200000 c 4500 | ||
|---|---|---|---|
| 001 | 1848950063 | ||
| 003 | DE-627 | ||
| 005 | 20230706203721.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 230614s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.3389/fendo.2023.1081741 |2 doi | |
| 035 | |a (DE-627)1848950063 | ||
| 035 | |a (DE-599)KXP1848950063 | ||
| 035 | |a (OCoLC)1389528691 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rda | ||
| 041 | |a eng | ||
| 084 | |a 33 |2 sdnb | ||
| 100 | 1 | |a Uglebjerg, Nicoline |e VerfasserIn |0 (DE-588)1292786507 |0 (DE-627)1849765367 |4 aut | |
| 245 | 1 | 0 | |a Four missense genetic variants in CUBN are associated with higher levels of eGFR in non-diabetes but not in diabetes mellitus or its subtypes |b A genetic association study in Europeans |c Nicoline Uglebjerg, Fariba Ahmadizar, Dina M. Aly, Marisa Cañadas-Garre, Claire Hill, Annemieke Naber, Asmundur Oddsson, Sunny S. Singh, Laura Smyth, David-Alexandre Trégouët, Layal Chaker, Mohsen Ghanbari, Valgerdur Steinthorsdottir, Emma Ahlqvist, Samy Hadjadj, Mandy Van Hoek, Maryam Kavousi, Amy Jayne McKnight, Eric J. Sijbrands, Kari Stefansson, Matias Simons, Peter Rossing and Tarunveer S. Ahluwalia |
| 264 | 1 | |c 28 February 2023 | |
| 300 | |a 11 | ||
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Gesehen am 14.06.2023 | ||
| 520 | |a AimRare genetic variants in the CUBN gene encoding the main albumin-transporter in the proximal tubule of the kidneys have previously been associated with microalbuminuria and higher urine albumin levels, also in diabetes. Sequencing studies in isolated proteinuria suggest that these variants might not affect kidney function, despite proteinuria. However, the relation of these CUBN missense variants to the estimated glomerular filtration rate (eGFR) is largely unexplored. We hereby broadly examine the associations between four CUBN missense variants and eGFRcreatinine in Europeans with Type 1 (T1D) and Type 2 Diabetes (T2D). Furthermore, we sought to deepen our understanding of these variants in a range of single- and aggregate- variant analyses of other kidney-related traits in individuals with and without diabetes mellitus.MethodsWe carried out a genetic association-based linear regression analysis between four CUBN missense variants (rs141640975, rs144360241, rs45551835, rs1801239) and eGFRcreatinine (ml/min/1.73 m2, CKD-EPIcreatinine(2012), natural log-transformed) in populations with T1D (n ~ 3,588) or T2D (n ~ 31,155) from multiple European studies and in individuals without diabetes from UK Biobank (UKBB, n ~ 370,061) with replication in deCODE (n = 127,090). Summary results of the diabetes-group were meta-analyzed using the fixed-effect inverse-variance method.ResultsAlbeit we did not observe associations between eGFRcreatinine and CUBN in the diabetes-group, we found significant positive associations between the minor alleles of all four variants and eGFRcreatinine in the UKBB individuals without diabetes with rs141640975 being the strongest (Effect=0.02, PeGFR_creatinine=2.2 × 10-9). We replicated the findings for rs141640975 in the Icelandic non-diabetes population (Effect=0.026, PeGFR_creatinine=7.7 × 10-4). For rs141640975, the eGFRcreatinine-association showed significant interaction with albuminuria levels (normo-, micro-, and macroalbuminuria; p = 0.03). An aggregated genetic risk score (GRS) was associated with higher urine albumin levels and eGFRcreatinine. The rs141640975 variant was also associated with higher levels of eGFRcreatinine-cystatin C (ml/min/1.73 m2, CKD-EPI2021, natural log-transformed) and lower circulating cystatin C levels.ConclusionsThe positive associations between the four CUBN missense variants and eGFR in a large population without diabetes suggests a pleiotropic role of CUBN as a novel eGFR-locus in addition to it being a known albuminuria-locus. Additional associations with diverse renal function measures (lower cystatin C and higher eGFRcreatinine-cystatin C levels) and a CUBN-focused GRS further suggests an important role of CUBN in the future personalization of chronic kidney disease management in people without diabetes. | ||
| 700 | 1 | |a Ahmadizar, Fariba |e VerfasserIn |4 aut | |
| 700 | 1 | |a Aly, Dina M. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Cañadas-Garre, Marisa |e VerfasserIn |4 aut | |
| 700 | 1 | |a Hill, Claire |e VerfasserIn |4 aut | |
| 700 | 1 | |a Naber, Annemieke |e VerfasserIn |4 aut | |
| 700 | 1 | |a Oddsson, Asmundur |e VerfasserIn |4 aut | |
| 700 | 1 | |a Singh, Sunny S. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Smyth, Laura |e VerfasserIn |4 aut | |
| 700 | 1 | |a Trégouët, David-Alexandre |e VerfasserIn |4 aut | |
| 700 | 1 | |a Chaker, Layal |e VerfasserIn |4 aut | |
| 700 | 1 | |a Ghanbari, Mohsen |e VerfasserIn |4 aut | |
| 700 | 1 | |a Steinthorsdottir, Valgerdur |e VerfasserIn |4 aut | |
| 700 | 1 | |a Ahlqvist, Emma |e VerfasserIn |4 aut | |
| 700 | 1 | |a Hadjadj, Samy |e VerfasserIn |4 aut | |
| 700 | 1 | |a Van Hoek, Mandy |e VerfasserIn |4 aut | |
| 700 | 1 | |a Kavousi, Maryam |e VerfasserIn |4 aut | |
| 700 | 1 | |a McKnight, Amy Jayne |e VerfasserIn |4 aut | |
| 700 | 1 | |a Sijbrands, Eric J. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Stefansson, Kari |e VerfasserIn |4 aut | |
| 700 | 1 | |a Simons, Matias |d 1975- |e VerfasserIn |0 (DE-588)124235646 |0 (DE-627)085726176 |0 (DE-576)29408035X |4 aut | |
| 700 | 1 | |a Rossing, Peter |e VerfasserIn |4 aut | |
| 700 | 1 | |a Ahluwalia, Tarun Veer Singh |e VerfasserIn |0 (DE-588)1241199485 |0 (DE-627)1770716955 |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Frontiers in endocrinology |d Lausanne : Frontiers Research Foundation, 2010 |g 14(2023), Artikel-ID 1081741, Seite 1-11 |h Online-Ressource |w (DE-627)645090948 |w (DE-600)2592084-4 |w (DE-576)336962975 |x 1664-2392 |7 nnas |a Four missense genetic variants in CUBN are associated with higher levels of eGFR in non-diabetes but not in diabetes mellitus or its subtypes A genetic association study in Europeans |
| 773 | 1 | 8 | |g volume:14 |g year:2023 |g elocationid:1081741 |g pages:1-11 |g extent:11 |a Four missense genetic variants in CUBN are associated with higher levels of eGFR in non-diabetes but not in diabetes mellitus or its subtypes A genetic association study in Europeans |
| 856 | 4 | 0 | |u https://doi.org/10.3389/fendo.2023.1081741 |x Resolving-System |x Verlag |z kostenfrei |3 Volltext |
| 856 | 4 | 0 | |u https://www.frontiersin.org/articles/10.3389/fendo.2023.1081741 |x Verlag |z kostenfrei |3 Volltext |
| 951 | |a AR | ||
| 992 | |a 20230614 | ||
| 993 | |a Article | ||
| 994 | |a 2023 | ||
| 998 | |g 124235646 |a Simons, Matias |m 124235646:Simons, Matias |d 910000 |d 911500 |e 910000PS124235646 |e 911500PS124235646 |k 0/910000/ |k 1/910000/911500/ |p 21 | ||
| 999 | |a KXP-PPN1848950063 |e 4336873828 | ||
| BIB | |a Y | ||
| SER | |a journal | ||
| JSO | |a {"language":["eng"],"recId":"1848950063","type":{"media":"Online-Ressource","bibl":"article-journal"},"note":["Gesehen am 14.06.2023"],"title":[{"subtitle":"A genetic association study in Europeans","title":"Four missense genetic variants in CUBN are associated with higher levels of eGFR in non-diabetes but not in diabetes mellitus or its subtypes","title_sort":"Four missense genetic variants in CUBN are associated with higher levels of eGFR in non-diabetes but not in diabetes mellitus or its subtypes"}],"person":[{"family":"Uglebjerg","given":"Nicoline","roleDisplay":"VerfasserIn","display":"Uglebjerg, Nicoline","role":"aut"},{"role":"aut","roleDisplay":"VerfasserIn","display":"Ahmadizar, Fariba","given":"Fariba","family":"Ahmadizar"},{"family":"Aly","given":"Dina M.","display":"Aly, Dina M.","roleDisplay":"VerfasserIn","role":"aut"},{"given":"Marisa","family":"Cañadas-Garre","role":"aut","roleDisplay":"VerfasserIn","display":"Cañadas-Garre, Marisa"},{"roleDisplay":"VerfasserIn","display":"Hill, Claire","role":"aut","family":"Hill","given":"Claire"},{"given":"Annemieke","family":"Naber","role":"aut","roleDisplay":"VerfasserIn","display":"Naber, Annemieke"},{"display":"Oddsson, Asmundur","roleDisplay":"VerfasserIn","role":"aut","family":"Oddsson","given":"Asmundur"},{"given":"Sunny S.","family":"Singh","role":"aut","roleDisplay":"VerfasserIn","display":"Singh, Sunny S."},{"family":"Smyth","given":"Laura","display":"Smyth, Laura","roleDisplay":"VerfasserIn","role":"aut"},{"role":"aut","roleDisplay":"VerfasserIn","display":"Trégouët, David-Alexandre","given":"David-Alexandre","family":"Trégouët"},{"role":"aut","roleDisplay":"VerfasserIn","display":"Chaker, Layal","given":"Layal","family":"Chaker"},{"display":"Ghanbari, Mohsen","roleDisplay":"VerfasserIn","role":"aut","family":"Ghanbari","given":"Mohsen"},{"role":"aut","display":"Steinthorsdottir, Valgerdur","roleDisplay":"VerfasserIn","given":"Valgerdur","family":"Steinthorsdottir"},{"display":"Ahlqvist, Emma","roleDisplay":"VerfasserIn","role":"aut","family":"Ahlqvist","given":"Emma"},{"given":"Samy","family":"Hadjadj","role":"aut","roleDisplay":"VerfasserIn","display":"Hadjadj, Samy"},{"family":"Van Hoek","given":"Mandy","roleDisplay":"VerfasserIn","display":"Van Hoek, Mandy","role":"aut"},{"role":"aut","display":"Kavousi, Maryam","roleDisplay":"VerfasserIn","given":"Maryam","family":"Kavousi"},{"given":"Amy Jayne","family":"McKnight","role":"aut","roleDisplay":"VerfasserIn","display":"McKnight, Amy Jayne"},{"family":"Sijbrands","given":"Eric J.","roleDisplay":"VerfasserIn","display":"Sijbrands, Eric J.","role":"aut"},{"role":"aut","display":"Stefansson, Kari","roleDisplay":"VerfasserIn","given":"Kari","family":"Stefansson"},{"family":"Simons","given":"Matias","roleDisplay":"VerfasserIn","display":"Simons, Matias","role":"aut"},{"family":"Rossing","given":"Peter","roleDisplay":"VerfasserIn","display":"Rossing, Peter","role":"aut"},{"role":"aut","roleDisplay":"VerfasserIn","display":"Ahluwalia, Tarun Veer Singh","given":"Tarun Veer Singh","family":"Ahluwalia"}],"relHost":[{"title":[{"title":"Frontiers in endocrinology","title_sort":"Frontiers in endocrinology"}],"pubHistory":["1.2010 -"],"part":{"pages":"1-11","year":"2023","extent":"11","volume":"14","text":"14(2023), Artikel-ID 1081741, Seite 1-11"},"titleAlt":[{"title":"Bone Research"},{"title":"Cancer Endocrinology"},{"title":"Cellular Endocrinology"},{"title":"Diabetes"},{"title":"Endocrinology of Aging"},{"title":"Experimental Endocrinology"},{"title":"Genomic Endocrinology"},{"title":"Molecular and Structural Endocrinology"},{"title":"Neuroendocrine Science"},{"title":"Pediatric Endocrinology"},{"title":"Pituitary Endocrinology"},{"title":"Systems and Translational Endocrinology"},{"title":"Thyroid Endocrinology"}],"disp":"Four missense genetic variants in CUBN are associated with higher levels of eGFR in non-diabetes but not in diabetes mellitus or its subtypes A genetic association study in EuropeansFrontiers in endocrinology","note":["Gesehen am 12.12.19","Specialty sections: Bone Research; Cancer Endocrinology; Cellular Endocrinology; Diabetes; Endocrinology of Aging; Experimental Endocrinology; Genomic Endocrinology; Molecular and Structural Endocrinology; Neuroendocrine Science; Pediatric Endocrinology; Pituitary Endocrinology; Systems and Translational Endocrinology; Thyroid Endocrinology"],"type":{"media":"Online-Ressource","bibl":"periodical"},"recId":"645090948","language":["eng"],"origin":[{"publisherPlace":"Lausanne","dateIssuedDisp":"2010-","publisher":"Frontiers Research Foundation","dateIssuedKey":"2010"}],"id":{"zdb":["2592084-4"],"eki":["645090948"],"issn":["1664-2392"]},"physDesc":[{"extent":"Online-Ressource"}]}],"physDesc":[{"extent":"11 S."}],"id":{"eki":["1848950063"],"doi":["10.3389/fendo.2023.1081741"]},"origin":[{"dateIssuedDisp":"28 February 2023","dateIssuedKey":"2023"}],"name":{"displayForm":["Nicoline Uglebjerg, Fariba Ahmadizar, Dina M. Aly, Marisa Cañadas-Garre, Claire Hill, Annemieke Naber, Asmundur Oddsson, Sunny S. Singh, Laura Smyth, David-Alexandre Trégouët, Layal Chaker, Mohsen Ghanbari, Valgerdur Steinthorsdottir, Emma Ahlqvist, Samy Hadjadj, Mandy Van Hoek, Maryam Kavousi, Amy Jayne McKnight, Eric J. Sijbrands, Kari Stefansson, Matias Simons, Peter Rossing and Tarunveer S. Ahluwalia"]}} | ||
| SRT | |a UGLEBJERGNFOURMISSEN2820 | ||