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Mayanja, R.* ; Machipisa, T.* ; Soremekun, O.* ; Kamiza, A.B.* ; Kintu, C.* ; Kalungi, A.* ; Kalyesubula, R.* ; Sande, O.J.* ; Jjingo, D.* ; Fabian, J.* ; Robinson-Cohen, C.* ; Franceschini, N.* ; Nitsch, D.* ; Nyirenda, M.* ; Zeggini, E. ; Morris, A.P.* ; Chikowore, T.* ; Fatumo, S.

Genome-wide association analysis of cystatin-C kidney function in continental Africa.

EBioMedicine 95:104775 (2023)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
BACKGROUND: Chronic kidney disease is becoming more prevalent in Africa, and its genetic determinants are poorly understood. Creatinine-based estimated glomerular filtration rate (eGFR) is commonly used to estimate kidney function, modelling the excretion of the endogenous biomarker (creatinine). However, eGFR based on creatinine has been shown to inadequately detect individuals with low kidney function in Sub-Saharan Africa, with eGFR based on cystatin-C (eGFRcys) exhibiting significantly superior performance. Therefore, we opted to conduct a GWAS for eGFRcys. METHODS: Using the Uganda Genomic Resource, we performed a genome-wide association study (GWAS) of eGFRcys in 5877 Ugandans and evaluated replication in independent studies. Subsequently, putative causal variants were screened through Bayesian fine-mapping. Functional annotation of the GWAS loci was performed using Functional Mapping and Annotation (FUMA). FINDINGS: Three independent lead single nucleotide polymorphisms (SNPs) (P-value <5 × 10-8 (based on likelihood ratio test (LRT))) were identified; rs59288815 (ANK3), rs4277141 (OR51B5) and rs911119 (CST3). From fine-mapping, rs59288815 and rs911119 each had a posterior probability of causality of >99%. The rs911119 SNP maps to the cystatin C gene and has been previously associated with eGFRcys among Europeans. With gene-set enrichment analyses of the olfactory receptor family 51 overlapping genes, we identified an association with the G-alpha-S signalling events. INTERPRETATION: Our study found two previously unreported associated SNPs for eGFRcys in continental Africans (rs59288815 and rs4277141) and validated a previously well-established SNP (rs911119) for eGFRcys. The identified gene-set enrichment for the G-protein signalling pathways relates to the capacity of the kidney to readily adapt to an ever-changing environment. Additional GWASs are required to represent the diverse regions in Africa. FUNDING: Wellcome (220740/Z/20/Z).
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Continental Africa ; Cystatin-c ; Estimated Glomerular Filtration Rate ; Fine-mapping ; Genome-wide Association Study ; Kidney Function; Glomerular-filtration-rate; Loci; Gene; Expression; Discovery; Ankyrin; Uganda
Sprache englisch
Veröffentlichungsjahr 2023
HGF-Berichtsjahr 2023
ISSN (print) / ISBN 2352-3964
e-ISSN 2352-3964
Zeitschrift EBioMedicine
Quellenangaben Band: 95, Heft: , Seiten: , Artikelnummer: 104775 Supplement: ,
Verlag Elsevier
Verlagsort Amsterdam [u.a.]
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Translational Genomics (ITG)
POF Topic(s) 30205 - Bioengineering and Digital Health
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-506700-001
Förderungen Wellcome Trust
DOI 10.1016/j.ebiom.2023.104775
WOS ID 001070492500001
Scopus ID 85169439059
PubMed ID 37639939
Erfassungsdatum 2023-10-06
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