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.
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.
EBioMedicine. 2023 Sep;95:104775. doi: 10.1016/j.ebiom.2023.104775. Epub 2023 Aug 26.
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.
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).
Three independent lead single nucleotide polymorphisms (SNPs) (P-value <5 × 10 (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.
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.
Wellcome (220740/Z/20/Z).
慢性肾脏病在非洲变得越来越普遍，但对其遗传决定因素知之甚少。基于肌酐的估计肾小球滤过率（eGFR）常用于估计肾功能，其模型基于内源性生物标志物（肌酐）的排泄。然而，基于肌酐的 eGFR 已被证明不能充分检测撒哈拉以南非洲地区肾功能低下的个体，基于半胱氨酸蛋白酶抑制剂-C（eGFRcys）的 eGFR 表现出显著更好的性能。因此，我们选择对 eGFRcys 进行全基因组关联研究（GWAS）。
利用乌干达基因组资源，我们对 5877 名乌干达人进行了 eGFRcys 的全基因组关联研究（GWAS），并在独立研究中进行了验证。随后，通过贝叶斯精细映射筛选潜在的因果变异。使用功能映射和注释（FUMA）对 GWAS 位点进行功能注释。
确定了三个独立的先导单核苷酸多态性（SNP）（基于似然比检验（LRT）的 P 值 <5×10）；rs59288815（ANK3）、rs4277141（OR51B5）和 rs911119（CST3）。从精细映射中，rs59288815 和 rs911119 各自的因果后验概率均>99%。rs911119 位于胱抑素 C 基因上，此前已被证明与欧洲人的 eGFRcys 相关。通过对嗅觉受体家族 51 重叠基因进行基因集富集分析，我们发现与 G-α-S 信号事件有关。
我们的研究在非洲大陆发现了两个以前未报道的与 eGFRcys 相关的 SNP（rs59288815 和 rs4277141），并验证了一个以前确定的与 eGFRcys 相关的 SNP（rs911119）。确定的 G 蛋白信号通路的基因集富集与肾脏适应不断变化的环境的能力有关。需要进行更多的 GWAS 来代表非洲的不同地区。
惠康信托基金（220740/Z/20/Z）。
