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

Richard Mayanja; Tafadzwa Machipisa; Opeyemi Soremekun; Abram B Kamiza; Christopher Kintu; Allan Kalungi; Robert Kalyesubula; Obondo J Sande; Daudi Jjingo; June Fabian; Cassianne Robinson-Cohen; Nora Franceschini; Dorothea Nitsch; Moffat Nyirenda; Eleftheria Zeggini; Andrew P Morris; Tinashe Chikowore; Segun Fatumo

doi:10.1016/j.ebiom.2023.104775

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

EBioMedicine. 2023 Sep:95:104775. doi: 10.1016/j.ebiom.2023.104775. Epub 2023 Aug 26.

Authors

Richard Mayanja¹, Tafadzwa Machipisa², Opeyemi Soremekun³, Abram B Kamiza⁴, Christopher Kintu¹, Allan Kalungi³, Robert Kalyesubula⁵, Obondo J Sande⁶, Daudi Jjingo⁷, June Fabian⁸, Cassianne Robinson-Cohen⁹, Nora Franceschini¹⁰, Dorothea Nitsch¹¹, Moffat Nyirenda¹², Eleftheria Zeggini¹³, Andrew P Morris¹⁴, Tinashe Chikowore¹⁵, Segun Fatumo¹⁶

Affiliations

¹ The African Computational Genomics (TACG) Research Group, MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda; Department of Immunology and Molecular Biology, School of Biomedical Sciences, Makerere University, College of Health Sciences, Kampala, Uganda.
² Department of Medicine, University of Cape Town & Groote Schuur Hospital, Cape Town, South Africa; Clinical Research Laboratory-Genetic and Molecular Epidemiology Laboratory (CRLB-GMEL), Population Health Research Institute (PHRI) & McMaster University, David Braley Cardiac, Vascular and Stroke Research Institute, 237 Barton Street East, Hamilton, Ontario, L8L 2X2, Canada.
³ The African Computational Genomics (TACG) Research Group, MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda.
⁴ The African Computational Genomics (TACG) Research Group, MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda; Malawi Epidemiology and Intervention Research Unit, Lilongwe, Malawi.
⁵ Medical Research Council/ Uganda Virus Research Institute (MRC/UVRI) and London School of Hygiene and Tropical Medicine (LSHTM) Uganda Research Unit, Entebbe, Uganda.
⁶ Department of Immunology and Molecular Biology, School of Biomedical Sciences, Makerere University, College of Health Sciences, Kampala, Uganda.
⁷ African Center of Excellence in Bioinformatics (ACE-B), Makerere University, Kampala, Uganda.
⁸ Medical Research Council/Wits University Rural Public Health and Health Transitions Research Unit (Agincourt), School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; Wits Donald Gordon Medical Centre, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
⁹ Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁰ Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
¹¹ London School of Hygiene and Tropical Medicine London, UK.
¹² Clinical Research Laboratory-Genetic and Molecular Epidemiology Laboratory (CRLB-GMEL), Population Health Research Institute (PHRI) & McMaster University, David Braley Cardiac, Vascular and Stroke Research Institute, 237 Barton Street East, Hamilton, Ontario, L8L 2X2, Canada; London School of Hygiene and Tropical Medicine London, UK.
¹³ Institute of Translational Genomics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; TUM School of Medicine, Translational Genomics, Technical University of Munich and Klinikum Rechts der Isar, Munich, Germany.
¹⁴ Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, Division of Musculoskeletal and Dermatological Sciences, The University of Manchester, Manchester, UK.
¹⁵ Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; MRC/Wits Developmental Pathways for Health Research Unit, Department of Pediatrics, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
¹⁶ The African Computational Genomics (TACG) Research Group, MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda; Medical Research Council/ Uganda Virus Research Institute (MRC/UVRI) and London School of Hygiene and Tropical Medicine (LSHTM) Uganda Research Unit, Entebbe, Uganda; London School of Hygiene and Tropical Medicine London, UK; Institute of Translational Genomics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany. Electronic address: segun.fatumo@lshtm.ac.uk.

Abstract

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).

Keywords: Continental Africa; Cystatin-C; Estimated glomerular filtration rate; Fine-mapping; Genome-wide association study; Kidney function.

MeSH terms

Bayes Theorem
Creatinine
Cystatin C* / genetics
Genome-Wide Association Study*
Humans
Kidney* / physiology
Uganda

Substances

Creatinine
Cystatin C

Abstract

MeSH terms

Substances

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