The causal effects of lipid traits on kidney function in Africans: bidirectional and multivariable Mendelian-randomization studyResearch in context
Summary: Background: Observational studies have investigated the effect of serum lipids on kidney function, but these findings are limited by confounding, reverse causation and have reported conflicting results. Mendelian randomization (MR) studies address this confounding problem. However, they ha...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-04-01
|
| Series: | EBioMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396423001020 |
| _version_ | 1797856435499958272 |
|---|---|
| author | Christopher Kintu Opeyemi Soremekun Abram B. Kamiza Allan Kalungi Richard Mayanja Robert Kalyesubula Bernard Bagaya S Daudi Jjingo June Fabian Dipender Gill Moffat Nyirenda Dorothea Nitsch Tinashe Chikowore Segun Fatumo |
| author_facet | Christopher Kintu Opeyemi Soremekun Abram B. Kamiza Allan Kalungi Richard Mayanja Robert Kalyesubula Bernard Bagaya S Daudi Jjingo June Fabian Dipender Gill Moffat Nyirenda Dorothea Nitsch Tinashe Chikowore Segun Fatumo |
| author_sort | Christopher Kintu |
| collection | DOAJ |
| description | Summary: Background: Observational studies have investigated the effect of serum lipids on kidney function, but these findings are limited by confounding, reverse causation and have reported conflicting results. Mendelian randomization (MR) studies address this confounding problem. However, they have been conducted mostly in European ancestry individuals. We, therefore, set out to investigate the effect of lipid traits on the estimated glomerular filtration rate (eGFR) based on serum creatinine in individuals of African ancestry. Methods: We used the two-sample and multivariable Mendelian randomization (MVMR) approaches; in which instrument variables (IV's) for the predictor (lipid traits) were derived from summary-level data of a meta-analyzed African lipid GWAS (MALG, n = 24,215) from the African Partnership for Chronic Disease Research (APCDR) (n = 13,612) & the Africa Wits-IN-DEPTH partnership for Genomics studies (AWI-Gen) dataset (n = 10,603). The outcome IV's were computed from the eGFR summary-level data of African-ancestry individuals within the Million Veteran Program (n = 57,336). A random-effects inverse variance method was used in our primary analysis, and pleiotropy was adjusted for using robust and penalized sensitivity testing. The lipid predictors for the MVMR were high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides (TG). Findings: We found a significant causal association between genetically predicted low-density lipoprotein (LDL) cholesterol and eGFR in African ancestry individuals β = 1.1 (95% CI [0.411–1.788]; p = 0.002). Similarly, total cholesterol (TC) showed a significant causal effect on eGFR β = 1.619 (95% CI [0.412–2.826]; p = 0.009). However, the IVW estimate showed that genetically predicted HDL-C β = −0.164, (95% CI = [−1.329 to 1.00]; p = 0.782), and TG β = −0.934 (CI = [−2.815 to 0.947]; p = 0.33) were not significantly causally associated with the risk of eGFR. In the multivariable analysis inverse-variance weighted (MVIVW) method, there was evidence for a causal association between LDL and eGFR β = 1.228 (CI = [0.477–1.979]; p = 0.001). A significant causal effect of Triglycerides (TG) on eGFR in the MVIVW analysis β = −1.3 ([−2.533 to −0.067]; p = 0.039) was observed as well. All the causal estimates reported reflect a unit change in the outcome per a 1 SD increase in the exposure. HDL showed no evidence of a significant causal association with eGFR in the MVIVW method (β = −0.117 (95% CI [−1.252 to 0.018]; p = 0.840)). We found no evidence of a reverse causal impact of eGFR on serum lipids. All our sensitivity analyses indicated no strong evidence of pleiotropy or heterogeneity between our instrumental variables for both the forward and reverse MR analysis. Interpretation: In this African ancestry population, genetically predicted higher LDL-C and TC are causally associated with higher eGFR levels, which may suggest that the relationship between LDL, TC and kidney function may be U-shaped. And as such, lowering LDL_C does not necessarily improve risk of kidney disease. This may also imply the reason why LDL_C is seen to be a poorer predictor of kidney function compared to HDL. In addition, this further supports that more work is warranted to confirm the potential association between lipid traits and risk of kidney disease in individuals of African Ancestry. Funding: Wellcome (220740/Z/20/Z). |
| first_indexed | 2024-04-09T20:40:23Z |
| format | Article |
| id | doaj.art-ace8b752a42f424aad2027fb1080f532 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-04-09T20:40:23Z |
| publishDate | 2023-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-ace8b752a42f424aad2027fb1080f5322023-03-30T04:26:37ZengElsevierEBioMedicine2352-39642023-04-0190104537The causal effects of lipid traits on kidney function in Africans: bidirectional and multivariable Mendelian-randomization studyResearch in contextChristopher Kintu0Opeyemi Soremekun1Abram B. Kamiza2Allan Kalungi3Richard Mayanja4Robert Kalyesubula5Bernard Bagaya S6Daudi Jjingo7June Fabian8Dipender Gill9Moffat Nyirenda10Dorothea Nitsch11Tinashe Chikowore12Segun Fatumo13The 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; MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, UgandaThe African Computational Genomics (TACG) Research Group, MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda; MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, UgandaThe African Computational Genomics (TACG) Research Group, MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, UgandaThe African Computational Genomics (TACG) Research Group, MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda; MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, UgandaThe African Computational Genomics (TACG) Research Group, MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda; MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, UgandaDepartment of Immunology and Molecular Biology, School of Biomedical Sciences, Makerere University College of Health Sciences, Kampala, Uganda; MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, UgandaDepartment of Immunology and Molecular Biology, School of Biomedical Sciences, Makerere University College of Health Sciences, Kampala, UgandaAfrican Center of Excellence in Bioinformatics (ACE-B), Makerere University, Kampala 10101, UgandaMedical 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 AfricaDepartment of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK; Chief Scientific Advisor Office, Research and Early Development, Novo Nordisk, Copenhagen, DenmarkMRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda; Department of Non-Communicable Disease Epidemiology, Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UKDepartment of Non-Communicable Disease Epidemiology, Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UKMRC/Wits Developmental Pathways for Health Research Unit, Department of Paediatrics, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South AfricaThe African Computational Genomics (TACG) Research Group, MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda; MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda; Department of Non-Communicable Disease Epidemiology, Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK; Corresponding author. MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda.Summary: Background: Observational studies have investigated the effect of serum lipids on kidney function, but these findings are limited by confounding, reverse causation and have reported conflicting results. Mendelian randomization (MR) studies address this confounding problem. However, they have been conducted mostly in European ancestry individuals. We, therefore, set out to investigate the effect of lipid traits on the estimated glomerular filtration rate (eGFR) based on serum creatinine in individuals of African ancestry. Methods: We used the two-sample and multivariable Mendelian randomization (MVMR) approaches; in which instrument variables (IV's) for the predictor (lipid traits) were derived from summary-level data of a meta-analyzed African lipid GWAS (MALG, n = 24,215) from the African Partnership for Chronic Disease Research (APCDR) (n = 13,612) & the Africa Wits-IN-DEPTH partnership for Genomics studies (AWI-Gen) dataset (n = 10,603). The outcome IV's were computed from the eGFR summary-level data of African-ancestry individuals within the Million Veteran Program (n = 57,336). A random-effects inverse variance method was used in our primary analysis, and pleiotropy was adjusted for using robust and penalized sensitivity testing. The lipid predictors for the MVMR were high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides (TG). Findings: We found a significant causal association between genetically predicted low-density lipoprotein (LDL) cholesterol and eGFR in African ancestry individuals β = 1.1 (95% CI [0.411–1.788]; p = 0.002). Similarly, total cholesterol (TC) showed a significant causal effect on eGFR β = 1.619 (95% CI [0.412–2.826]; p = 0.009). However, the IVW estimate showed that genetically predicted HDL-C β = −0.164, (95% CI = [−1.329 to 1.00]; p = 0.782), and TG β = −0.934 (CI = [−2.815 to 0.947]; p = 0.33) were not significantly causally associated with the risk of eGFR. In the multivariable analysis inverse-variance weighted (MVIVW) method, there was evidence for a causal association between LDL and eGFR β = 1.228 (CI = [0.477–1.979]; p = 0.001). A significant causal effect of Triglycerides (TG) on eGFR in the MVIVW analysis β = −1.3 ([−2.533 to −0.067]; p = 0.039) was observed as well. All the causal estimates reported reflect a unit change in the outcome per a 1 SD increase in the exposure. HDL showed no evidence of a significant causal association with eGFR in the MVIVW method (β = −0.117 (95% CI [−1.252 to 0.018]; p = 0.840)). We found no evidence of a reverse causal impact of eGFR on serum lipids. All our sensitivity analyses indicated no strong evidence of pleiotropy or heterogeneity between our instrumental variables for both the forward and reverse MR analysis. Interpretation: In this African ancestry population, genetically predicted higher LDL-C and TC are causally associated with higher eGFR levels, which may suggest that the relationship between LDL, TC and kidney function may be U-shaped. And as such, lowering LDL_C does not necessarily improve risk of kidney disease. This may also imply the reason why LDL_C is seen to be a poorer predictor of kidney function compared to HDL. In addition, this further supports that more work is warranted to confirm the potential association between lipid traits and risk of kidney disease in individuals of African Ancestry. Funding: Wellcome (220740/Z/20/Z).http://www.sciencedirect.com/science/article/pii/S2352396423001020Serum lipidseGFRChronic kidney diseaseKidney functionTwo-sample Mendelian Randomization |
| spellingShingle | Christopher Kintu Opeyemi Soremekun Abram B. Kamiza Allan Kalungi Richard Mayanja Robert Kalyesubula Bernard Bagaya S Daudi Jjingo June Fabian Dipender Gill Moffat Nyirenda Dorothea Nitsch Tinashe Chikowore Segun Fatumo The causal effects of lipid traits on kidney function in Africans: bidirectional and multivariable Mendelian-randomization studyResearch in context EBioMedicine Serum lipids eGFR Chronic kidney disease Kidney function Two-sample Mendelian Randomization |
| title | The causal effects of lipid traits on kidney function in Africans: bidirectional and multivariable Mendelian-randomization studyResearch in context |
| title_full | The causal effects of lipid traits on kidney function in Africans: bidirectional and multivariable Mendelian-randomization studyResearch in context |
| title_fullStr | The causal effects of lipid traits on kidney function in Africans: bidirectional and multivariable Mendelian-randomization studyResearch in context |
| title_full_unstemmed | The causal effects of lipid traits on kidney function in Africans: bidirectional and multivariable Mendelian-randomization studyResearch in context |
| title_short | The causal effects of lipid traits on kidney function in Africans: bidirectional and multivariable Mendelian-randomization studyResearch in context |
| title_sort | causal effects of lipid traits on kidney function in africans bidirectional and multivariable mendelian randomization studyresearch in context |
| topic | Serum lipids eGFR Chronic kidney disease Kidney function Two-sample Mendelian Randomization |
| url | http://www.sciencedirect.com/science/article/pii/S2352396423001020 |
| work_keys_str_mv | AT christopherkintu thecausaleffectsoflipidtraitsonkidneyfunctioninafricansbidirectionalandmultivariablemendelianrandomizationstudyresearchincontext AT opeyemisoremekun thecausaleffectsoflipidtraitsonkidneyfunctioninafricansbidirectionalandmultivariablemendelianrandomizationstudyresearchincontext AT abrambkamiza thecausaleffectsoflipidtraitsonkidneyfunctioninafricansbidirectionalandmultivariablemendelianrandomizationstudyresearchincontext AT allankalungi thecausaleffectsoflipidtraitsonkidneyfunctioninafricansbidirectionalandmultivariablemendelianrandomizationstudyresearchincontext AT richardmayanja thecausaleffectsoflipidtraitsonkidneyfunctioninafricansbidirectionalandmultivariablemendelianrandomizationstudyresearchincontext AT robertkalyesubula thecausaleffectsoflipidtraitsonkidneyfunctioninafricansbidirectionalandmultivariablemendelianrandomizationstudyresearchincontext AT bernardbagayas thecausaleffectsoflipidtraitsonkidneyfunctioninafricansbidirectionalandmultivariablemendelianrandomizationstudyresearchincontext AT daudijjingo thecausaleffectsoflipidtraitsonkidneyfunctioninafricansbidirectionalandmultivariablemendelianrandomizationstudyresearchincontext AT junefabian thecausaleffectsoflipidtraitsonkidneyfunctioninafricansbidirectionalandmultivariablemendelianrandomizationstudyresearchincontext AT dipendergill thecausaleffectsoflipidtraitsonkidneyfunctioninafricansbidirectionalandmultivariablemendelianrandomizationstudyresearchincontext AT moffatnyirenda thecausaleffectsoflipidtraitsonkidneyfunctioninafricansbidirectionalandmultivariablemendelianrandomizationstudyresearchincontext AT dorotheanitsch thecausaleffectsoflipidtraitsonkidneyfunctioninafricansbidirectionalandmultivariablemendelianrandomizationstudyresearchincontext AT tinashechikowore thecausaleffectsoflipidtraitsonkidneyfunctioninafricansbidirectionalandmultivariablemendelianrandomizationstudyresearchincontext AT segunfatumo thecausaleffectsoflipidtraitsonkidneyfunctioninafricansbidirectionalandmultivariablemendelianrandomizationstudyresearchincontext AT christopherkintu causaleffectsoflipidtraitsonkidneyfunctioninafricansbidirectionalandmultivariablemendelianrandomizationstudyresearchincontext AT opeyemisoremekun causaleffectsoflipidtraitsonkidneyfunctioninafricansbidirectionalandmultivariablemendelianrandomizationstudyresearchincontext AT abrambkamiza causaleffectsoflipidtraitsonkidneyfunctioninafricansbidirectionalandmultivariablemendelianrandomizationstudyresearchincontext AT allankalungi causaleffectsoflipidtraitsonkidneyfunctioninafricansbidirectionalandmultivariablemendelianrandomizationstudyresearchincontext AT richardmayanja causaleffectsoflipidtraitsonkidneyfunctioninafricansbidirectionalandmultivariablemendelianrandomizationstudyresearchincontext AT robertkalyesubula causaleffectsoflipidtraitsonkidneyfunctioninafricansbidirectionalandmultivariablemendelianrandomizationstudyresearchincontext AT bernardbagayas causaleffectsoflipidtraitsonkidneyfunctioninafricansbidirectionalandmultivariablemendelianrandomizationstudyresearchincontext AT daudijjingo causaleffectsoflipidtraitsonkidneyfunctioninafricansbidirectionalandmultivariablemendelianrandomizationstudyresearchincontext AT junefabian causaleffectsoflipidtraitsonkidneyfunctioninafricansbidirectionalandmultivariablemendelianrandomizationstudyresearchincontext AT dipendergill causaleffectsoflipidtraitsonkidneyfunctioninafricansbidirectionalandmultivariablemendelianrandomizationstudyresearchincontext AT moffatnyirenda causaleffectsoflipidtraitsonkidneyfunctioninafricansbidirectionalandmultivariablemendelianrandomizationstudyresearchincontext AT dorotheanitsch causaleffectsoflipidtraitsonkidneyfunctioninafricansbidirectionalandmultivariablemendelianrandomizationstudyresearchincontext AT tinashechikowore causaleffectsoflipidtraitsonkidneyfunctioninafricansbidirectionalandmultivariablemendelianrandomizationstudyresearchincontext AT segunfatumo causaleffectsoflipidtraitsonkidneyfunctioninafricansbidirectionalandmultivariablemendelianrandomizationstudyresearchincontext |