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; MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda.
The African Computational Genomics (TACG) Research Group, MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda; MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda.
EBioMedicine. 2023 Apr;90:104537. doi: 10.1016/j.ebiom.2023.104537. Epub 2023 Mar 29.
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).
背景：观察性研究已经探讨了血清脂质对肾功能的影响，但这些发现受到混杂因素、反向因果关系的限制，并且报告的结果相互矛盾。孟德尔随机化 (MR) 研究解决了这个混杂问题。然而，它们主要在欧洲血统个体中进行。因此，我们着手研究基于非洲血统个体中血清肌酐的估计肾小球滤过率 (eGFR) 的脂质特征的影响。
方法：我们使用两样本和多变量孟德尔随机化 (MVMR) 方法；其中，预测因子（脂质特征）的工具变量 (IV) 源自非洲脂质 GWAS 的汇总数据（MALG，n=24,215）来自非洲慢性病研究伙伴关系 (APCDR)（n=13,612）和非洲威特斯-深入伙伴关系基因组学研究 (AWI-Gen) 数据集（n=10,603）。eGFR 的汇总水平数据来自百万退伍军人计划（n=57,336）中的非洲血统个体。在我们的主要分析中，使用了随机效应逆方差方法，并且使用稳健和惩罚敏感测试来调整多效性。MVMR 的脂质预测因子是高密度脂蛋白 (HDL) 胆固醇、低密度脂蛋白 (LDL) 胆固醇和甘油三酯 (TG)。
结果：我们发现，在非洲血统个体中，遗传预测的 LDL 胆固醇与 eGFR 之间存在显著的因果关联β=1.1（95%CI[0.411-1.788]；p=0.002）。同样，总胆固醇 (TC) 对 eGFR 也表现出显著的因果影响β=1.619（95%CI[0.412-2.826]；p=0.009）。然而，IVW 估计表明，遗传预测的 HDL-Cβ=-0.164（95%CI=-1.329 至 1.00），TGβ=-0.934（95%CI=-2.815 至 0.947）与 eGFR 的风险没有显著的因果关系。在多变量分析中，逆方差加权（MVIVW）方法表明，LDL 与 eGFR 之间存在因果关系β=1.228（95%CI[0.477-1.979]；p=0.001）。在 MVIVW 分析中，甘油三酯 (TG) 对 eGFR 也有显著的因果作用β=-1.3（95%CI=-2.533 至-0.067）。所有报告的因果估计值反映了暴露量每增加一个标准差，结局就会相应变化一个单位。HDL 在 MVIVW 方法中与 eGFR 没有显著的因果关系（β=-0.117（95%CI=-1.252 至 0.018）；p=0.840）。我们没有发现 eGFR 对血清脂质有反向因果影响的证据。我们所有的敏感性分析都表明，在正向和反向 MR 分析中，我们的工具变量之间没有明显的多效性或异质性。
解释：在这个非洲血统人群中，遗传预测的 LDL-C 和 TC 水平升高与 eGFR 水平升高有因果关系，这可能表明 LDL、TC 和肾功能之间的关系可能是 U 形的。因此，降低 LDL-C 不一定能降低肾脏疾病的风险。这也可能解释了为什么 LDL-C 作为肾功能的预测指标不如 HDL 好。此外，这进一步支持了在非洲血统个体中，需要进行更多的工作来确认脂质特征与肾脏疾病风险之间的潜在关联。
资金：惠康基金会（220740/Z/20/Z）。
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