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Four missense genet...
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
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- Uglebjerg, Nicoline (author)
- Steno Diabetes Center Copenhagen
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- Ahmadizar, Fariba (author)
- University Medical Center Utrecht,Erasmus University Medical Center
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- Aly, Dina M. (author)
- Lund University,Lunds universitet,Translationell muskelforskning,Forskargrupper vid Lunds universitet,Translational Muscle Research,Lund University Research Groups
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- Cañadas-Garre, Marisa (author)
- Andalusian School Of Public Health (EASP),University of Granada,Queen's University Belfast
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- Hill, Claire (author)
- Queen's University Belfast
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- Naber, Annemieke (author)
- Erasmus University Medical Center
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- Oddsson, Asmundur (author)
- deCODE Genetics
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- Singh, Sunny S. (author)
- Erasmus University Medical Center
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- Smyth, Laura (author)
- Queen's University Belfast
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- Trégouët, David Alexandre (author)
- Bordeaux Population Health Centre
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- Chaker, Layal (author)
- Erasmus University Medical Center
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- Ghanbari, Mohsen (author)
- Erasmus University Medical Center
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- Steinthorsdottir, Valgerdur (author)
- deCODE Genetics
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- Ahlqvist, Emma (author)
- Lund University,Lunds universitet,Translationell muskelforskning,Forskargrupper vid Lunds universitet,Translational Muscle Research,Lund University Research Groups
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- Hadjadj, Samy (author)
- Nantes University Hospital,University of Nantes
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- Van Hoek, Mandy (author)
- Erasmus University Medical Center
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- Kavousi, Maryam (author)
- Erasmus University Medical Center
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- McKnight, Amy Jayne (author)
- Queen's University Belfast
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- Sijbrands, Eric J. (author)
- Erasmus University Medical Center
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- Stefansson, Kari (author)
- University of Iceland,deCODE Genetics
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- Simons, Matias (author)
- University Hospital Heidelberg
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- Rossing, Peter (author)
- University of Copenhagen,Steno Diabetes Center Copenhagen
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- Ahluwalia, Tarunveer S. (author)
- University of Copenhagen,Steno Diabetes Center Copenhagen
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(creator_code:org_t)
- 2023-02-28
- 2023
- English.
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In: Frontiers in Endocrinology. - : Frontiers Media SA. - 1664-2392. ; 14
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Abstract
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- Aim: Rare 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. Methods: We 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. Results: Albeit 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. Conclusions: The 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
Keyword
- chronic kidney disease (CKD)
- cubilin
- CUBN
- diabetes
- eGFR
- genetics
- kidney function
- non-diabetes
Publication and Content Type
- art (subject category)
- ref (subject category)
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Uglebjerg, Nicol ...
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Ahmadizar, Farib ...
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Aly, Dina M.
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Cañadas-Garre, M ...
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Hill, Claire
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Naber, Annemieke
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show more...
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Oddsson, Asmundu ...
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Singh, Sunny S.
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Smyth, Laura
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Trégouët, David ...
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Chaker, Layal
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Ghanbari, Mohsen
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Steinthorsdottir ...
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Ahlqvist, Emma
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Hadjadj, Samy
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Van Hoek, Mandy
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Kavousi, Maryam
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McKnight, Amy Ja ...
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Sijbrands, Eric ...
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Stefansson, Kari
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Simons, Matias
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Rossing, Peter
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Ahluwalia, Tarun ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Endocrinology an ...
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Frontiers in End ...
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Lund University