Ngo-Bitoungui Valentina J, Belinga Suzanne, Mnika Khuthala, Masekoameng Tshepiso, Nembaware Victoria, Essomba René G, Ngo-Sack Francoise, Awandare Gordon, Mazandu Gaston K, Wonkam Ambroise
West African Centre for Cell Biology of Infectious Pathogens, University of Ghana, Legon-Accra, Ghana.
Division of Human Genetics, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
Front Genet. 2021 Mar 15;12:595702. doi: 10.3389/fgene.2021.595702. eCollection 2021.
Renal dysfunctions are associated with increased morbidity and mortality in sickle cell disease (SCD). Early detection and subsequent management of SCD patients at risk for renal failure and dysfunctions are essential, however, predictors that can identify patients at risk of developing renal dysfunction are not fully understood.
In this study, we have investigated the association of 31 known kidney dysfunctions-related variants detected in African Americans from multi-ethnic genome wide studies (GWAS) meta-analysis, to kidney-dysfunctions in a group of 413 Cameroonian patients with SCD. Systems level bioinformatics analyses were performed, employing protein-protein interaction networks to further interrogate the putative associations.
Up to 61% of these patients had micro-albuminuria, 2.4% proteinuria, 71% glomerular hyperfiltration, and 5.9% had renal failure. Six variants are significantly associated with the two quantifiable phenotypes of kidney dysfunction (eGFR and crude-albuminuria): ( = 0.02020), - ( = 0.04208), and ( = 0.04610) are associated with eGFR; and ( = 0.03730), ( = 0.02340), and ( = 0.03803) observed to be protective against micro-albuminuria. We identified a protein-protein interaction sub-network containing three of these gene variants: , and , connected to the Nuclear factor NF-kappa-B p105 subunit (NFKB1), revealed to be essential and might indirectly influence extreme phenotypes. Interestingly, clinical variables, including body mass index (BMI), systolic blood pressure, vaso-occlusive crisis (VOC), and haemoglobin (Hb), explain better the kidney phenotypic variations in this SCD population.
This study highlights a strong contribution of haematological indices (Hb level), anthropometric variables (BMI, blood pressure), and clinical events (i.e., vaso-occlusive crisis) to kidney dysfunctions in SCD, rather than known genetic factors. Only 6/31 characterised gene-variants are associated with kidney dysfunction phenotypes in SCD samples from Cameroon. The data reveal and emphasise the urgent need to extend GWAS studies in populations of African ancestries living in Africa, and particularly for kidney dysfunctions in SCD.
肾功能障碍与镰状细胞病（SCD）的发病率和死亡率增加相关。然而，早期发现并随后管理有肾衰竭和功能障碍风险的SCD患者至关重要，但尚未完全了解可识别有发生肾功能障碍风险患者的预测因素。
在本研究中，我们调查了在多民族全基因组研究（GWAS）荟萃分析中在非裔美国人中检测到的31个已知的与肾功能障碍相关的变异与一组413名喀麦隆SCD患者的肾功能障碍之间的关联。进行了系统水平的生物信息学分析，利用蛋白质-蛋白质相互作用网络进一步探究假定的关联。
这些患者中高达61%有微量白蛋白尿，2.4%有蛋白尿，71%有肾小球高滤过，5.9%有肾衰竭。六个变异与肾功能障碍的两种可量化表型（估算肾小球滤过率和粗白蛋白尿）显著相关： （ = 0.02020）、 - （ = 0.04208）和 （ = 0.04610）与估算肾小球滤过率相关； （ = 0.03730）、 （ = 0.02340）和 （ = 0.03803）被观察到对微量白蛋白尿有保护作用。我们确定了一个蛋白质-蛋白质相互作用子网，其中包含这些基因变异中的三个： 、 和 ，它们与核因子NF-κB p105亚基（NFKB1）相连，显示该亚基至关重要，可能间接影响极端表型。有趣的是，临床变量，包括体重指数（BMI）、收缩压、血管闭塞性危机（VOC）和血红蛋白（Hb），能更好地解释该SCD人群的肾脏表型变异。
本研究强调血液学指标（Hb水平）、人体测量变量（BMI、血压）和临床事件（即血管闭塞性危机）对SCD患者肾功能障碍的影响很大，而非已知的遗传因素。在喀麦隆SCD样本中，31个已鉴定的基因变异中只有6个与肾功能障碍表型相关。数据揭示并强调迫切需要在生活在非洲的非洲裔人群中扩展GWAS研究，特别是针对SCD患者的肾功能障碍研究。
