Apolipoprotein L1 Variants and Blood Pressure Traits in African Americans

Nadkarni, Girish N.; Galarneau, Geneviève; Ellis, Stephen B.; Nadukuru, Rajiv; Zhang, Jinglan; Scott, Stuart A.; Schurmann, Claudia; Li, Rongling; Rasmussen‐Torvik, Laura J.; Kho, Abel N.; Hayes, M. Geoffrey; Pacheco, Jennifer A.; Manolio, Teri A.; Chisholm, Rex L.; Roden, Dan M.; Denny, Joshua C.; Kenny, Eimear E.; Böttinger, Erwin P.

doi:10.1016/j.jacc.2017.01.040

Cited by 55 publications

(43 citation statements)

References 38 publications

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“…HIVAN also is effectively prevented and treated with antiretroviral medication, which functions to both suppress viral replication and restore the immune system. However, human studies that specifically investigated a link between CKD risk and APOL1 expression did not find an association with circulating APOL1 protein levels in both HIV-infected and uninfected cohorts (3,43). In general, systemic and acutely high levels of interferons routinely occur throughout life with any viral infection, including the common cold and flu.…”

Section: Gene-environment Interaction and Second-hit Stressorsmentioning

confidence: 99%

APOL1 polymorphisms and kidney disease: loss-of-function or gain-of-function?

Bruggeman

O’Toole

Sedor

2019

American Journal of Physiology-Renal Physiology

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The mechanism that explains the association of APOL1 variants with nondiabetic kidney diseases in African Americans remains unclear. Kidney disease risk is inherited as a recessive trait, and many studies investigating the intracellular function of APOL1 have indicated the APOL1 variants G1 and G2 are associated with cytotoxicity. Whether cytotoxicity results from the absence of a protective effect conferred by the G0 allele or is induced by a deleterious effect of variant allele expression has not be conclusively established. A central issue hampering basic biology studies is the lack of model systems that authentically replicate APOL1 expression patterns. APOL1 is present in humans and a few other primates and appears to have important functions in the kidney, as the kidney is the primary target for disease associated with the genetic variance. There have been no studies to date assessing the function of untagged APOL1 protein under native expression in human or primate kidney cells, and no studies have examined the heterozygous state, a disease-free condition in humans. A second major issue is the chronic kidney disease (CKD)-associated APOL1 variants are conditional mutations, where the disease-inducing function is only evident under the appropriate environmental stimulus. In addition, it is possible there may be more than one mechanism of pathogenesis that is dependent on the nature of the stressor or other genetic variabilities. Studies addressing the function of APOL1 and how the CKD-associated APOL1 variants cause kidney disease are challenging and remain to be fully investigated under conditions that faithfully model known human genetics and physiology.

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Section: Gene-environment Interaction and Second-hit Stressorsmentioning

confidence: 99%

APOL1 polymorphisms and kidney disease: loss-of-function or gain-of-function?

Bruggeman

O’Toole

Sedor

2019

American Journal of Physiology-Renal Physiology

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“…The BioMe Biobank Program of The Charles Bronfman Institute for Personalized Medicine started in 2007 at the ISMMS. 40,41 We randomly selected 997 BioMe participants with type 2 diabetes, a baseline eGFR between 45 and 90 ml/min per 1.73 m 2 at the time of BioMe enrollment, and at least 3 years of follow-up data in the electronic health record. We defined the baseline period as 1 year before the BioMe enrollment date.…”

Section: Clinical Cohort and Analysesmentioning

confidence: 99%

LRG1 Promotes Diabetic Kidney Disease Progression by Enhancing TGF-β–Induced Angiogenesis

Hong

Lü

et al. 2019

JASN

Self Cite

104

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Background Glomerular endothelial dysfunction and neoangiogenesis have long been implicated in the pathogenesis of diabetic kidney disease (DKD). However, the specific molecular pathways contributing to these processes in the early stages of DKD are not well understood. Our recent transcriptomic profiling of glomerular endothelial cells identified a number of proangiogenic genes that were upregulated in diabetic mice, including leucine-rich a-2-glycoprotein 1 (LRG1). LRG1 was previously shown to promote neovascularization in mouse models of ocular disease by potentiating endothelial TGF-b/activin receptorlike kinase 1 (ALK1) signaling. However, LRG1's role in the kidney, particularly in the setting of DKD, has been unclear.Methods We analyzed expression of LRG1 mRNA in glomeruli of diabetic kidneys and assessed its localization by RNA in situ hybridization. We examined the effects of genetic ablation of Lrg1 on DKD progression in unilaterally nephrectomized, streptozotocin-induced diabetic mice at 12 and 20 weeks after diabetes induction. We also assessed whether plasma LRG1 was associated with renal outcome in patients with type 2 diabetes.Results LRG1 localized predominantly to glomerular endothelial cells, and its expression was elevated in the diabetic kidneys. LRG1 ablation markedly attenuated diabetes-induced glomerular angiogenesis, podocyte loss, and the development of diabetic glomerulopathy. These improvements were associated with reduced ALK1-Smad1/5/8 activation in glomeruli of diabetic mice. Moreover, increased plasma LRG1 was associated with worse renal outcome in patients with type 2 diabetes.Conclusions These findings identify LRG1 as a potential novel pathogenic mediator of diabetic glomerular neoangiogenesis and a risk factor in DKD progression.Diabetic kidney disease (DKD) is a frequent complication of diabetes mellitus (DM) and the most common cause of ESRD in the United States. 1 Intensive glycemic control, BP control, and blockade of the renin-angiotensin-aldosterone system are the gold standard for current treatment of patients with DKD. 2-4 However, these established regimens provide only partial therapeutic effects, 5 indicating that pathogenic mechanisms driving DKD progression may not be targeted by current treatments. In addition, several recent clinical trials in DKD treatments were unsuccessful, 5-8 highlighting an unmet need for better understanding of mechanisms mediating the early stages of DKD for the design of novel preventive therapeutic strategies.Lrg1 expression that colocalize with CD31 outside the tubules. Scale bars, 20 mm. (D) Semiquantitative scoring of Lrg1 mRNA colocalized with Pecam mRNA (n=3 mice per group, 20 gloms scored per mouse). (E) In situ hybridization of LRG1 mRNA (red) combined with CD31 immunofluorescence (green) on human kidney sections with nuclear counterstain. Glomeruli are outlined with dotted lines on upper panels, and magnified view of the box is shown in lower panels. Scale bar, 50 mm. (F) Semiquantitative scoring of LRG1 mRNA colocalized with CD31...

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“…APOL1 risk alleles are associated with higher systolic blood pressure and earlier hypertension diagnoses in young Afro-Americans [24]. In our study, 88% of our patients had a diagnostic of arterial hypertension.…”

mentioning

confidence: 44%

Prevalence of APOL1 Risk Variants in Afro-Descendant Patients with Chronic Kidney Disease in a Latin American Country

Durán

Ramı́rez

Posada

et al. 2019

International Journal of Nephrology

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Introduction. In Colombia, the genetic background of the populations was shaped by different levels of admixture between Natives, European, and Africans. Approximately 35.363 patients have diagnosed chronic kidney disease and according to population studies, 10.4% of these patients are Afro-descendant. We aim to assess the frequency of APOL1 variants G1 and G2 in Afro-descendant patients with ESRD treated at la Fundacion Valle del Lili University Hospital in Cali, Colombia. Methods. This is an observational cross-sectional study. Afro-descendant patients with ESRD in waitlist or recipients of kidney transplant were evaluated. Clinical data were collected from the electronic medical records. Genotyping was carried out by amplification of the exon 7 of the APOL1 gene. For the identification of risk genotypes, the bioinformatics tool BLAST was used. Results. We enrolled 102 participants. The frequency of APOL1 risk variants was 67.2%, in which 24.5% (n = 25) were G1 heterozygous and 5.8% (n = 6) were G2 heterozygous and 37% of the patients had high-risk status with two alleles in homozygous (G1/G1 = 21 and G2/G2 = 3) or compound heterozygote (G1/G2 = 14) form.

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Apolipoprotein L1 Variants and Blood Pressure Traits in African Americans

Cited by 55 publications

References 38 publications

APOL1 polymorphisms and kidney disease: loss-of-function or gain-of-function?

APOL1 polymorphisms and kidney disease: loss-of-function or gain-of-function?

LRG1 Promotes Diabetic Kidney Disease Progression by Enhancing TGF-β–Induced Angiogenesis

Prevalence of APOL1 Risk Variants in Afro-Descendant Patients with Chronic Kidney Disease in a Latin American Country

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