Re-Sequencing of the &lt;b&gt;&lt;i&gt;APOL1&lt;/i&gt;&lt;/b&gt;-&lt;b&gt;&lt;i&gt;APOL4&lt;/i&gt;&lt;/b&gt; and &lt;b&gt;&lt;i&gt;MYH9&lt;/i&gt;&lt;/b&gt; Gene Regions in African Americans Does Not Identify Additional Risks for CKD Progression

Hawkins, Gregory A.; Friedman, David J.; Lu, Lingyi; McWilliams, David R.; Chou, Jeff W.; Sajuthi, Satria; Divers, Jasmin; Parekh, Rulan S.; Li, Man; Pollack, Martin R.; Hicks, Pamela J.; Bowden, Donald W.; Ma, Lijun; Freedman, Barry I.; Langefeld, Carl D.

doi:10.1159/000439448

Cited by 13 publications

(10 citation statements)

References 26 publications

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“…6). Variants have been identified in AAs in other genes identified in our study, including APOL3 46. Future work lies in identifying variants in the 3′ UTRs of the identified mRNAs in the miRNA:mRNA pairs discussed in this study and whether they functionally influence gene expression in our cohort or in the pathways that are differentially-expressed between AA and white hypertensive women.…”

Section: Discussionmentioning

confidence: 74%

Racial differences in microRNA and gene expression in hypertensive women

Dluzen

Hooten

Zhang

et al. 2016

Sci Rep

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Systemic arterial hypertension is an important cause of cardiovascular disease morbidity and mortality. African Americans are disproportionately affected by hypertension, in fact the incidence, prevalence, and severity of hypertension is highest among African American (AA) women. Previous data suggests that differential gene expression influences individual susceptibility to selected diseases and we hypothesized that this phenomena may affect health disparities in hypertension. Transcriptional profiling of peripheral blood mononuclear cells from AA or white, normotensive or hypertensive females identified thousands of mRNAs differentially-expressed by race and/or hypertension. Predominant gene expression differences were observed in AA hypertensive females compared to AA normotensives or white hypertensives. Since microRNAs play important roles in regulating gene expression, we profiled global microRNA expression and observed differentially-expressed microRNAs by race and/or hypertension. We identified novel mRNA-microRNA pairs potentially involved in hypertension-related pathways and differently-expressed, including MCL1/miR-20a-5p, APOL3/miR-4763-5p, PLD1/miR-4717-3p, and PLD1/miR-4709-3p. We validated gene expression levels via RT-qPCR and microRNA target validation was performed in primary endothelial cells. Altogether, we identified significant gene expression differences between AA and white female hypertensives and pinpointed novel mRNA-microRNA pairs differentially-expressed by hypertension and race. These differences may contribute to the known disparities in hypertension and may be potential targets for intervention.

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Section: Discussionmentioning

confidence: 74%

Racial differences in microRNA and gene expression in hypertensive women

Dluzen

Hooten

Zhang

et al. 2016

Sci Rep

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“…In the genotyping of APOL1 G1 and G2, we detected a higher allele frequency (20%) of the rs16996616 SNP (Asp337Asn) in ESKD cases and controls in the Kinshasa cohort than the frequency reported for other regions of Africa (8%) [20, 21]. This SNP was not found to be associated with hypertension-attributed nephropathy in Kinshasa or in other studies [20, 21]. In light of the finding that individuals heterozygous for G1 were also heterozygous for Asp337Asn, we sought to determine the haplotype background in which this SNP arose.…”

Section: Resultsmentioning

confidence: 87%

G1 is the major APOL1 risk allele for hypertension-attributed nephropathy in Central Africa

Sumaili

Shemer

Kruzel-Davila

et al. 2018

Clinical Kidney Journal

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Background Sub-Saharan Africans exhibit a higher frequency of chronic kidney disease (CKD) than other populations. In this study, we sought to determine the frequency of apolipoprotein L1 ( APOL1 ) genotypes in hypertension-attributed CKD in Kinshasa, Democratic Republic of the Congo. Methods We performed a case–control study identifying 162 subjects: 79 with hypertension-attributed CKD and 83 controls living in Kinshasa who were genotyped for APOL1 risk variants between July 2013 and November 2016. We selected control subjects from the general population and matched them with the cases according to age. Logistic regression analysis was used to examine the relationship between APOL1 high-risk genotypes and CKD. Results The frequencies of the APOL1 G1 and G2 alleles were 19.1 and 7.1%, respectively. The number of individuals with the G1 and G2 risk alleles was significantly higher in the CKD group (12.7%) than in the control group (2.4%), particularly in individuals with end-stage kidney disease (14.3%). Subjects carrying two risk alleles was strongly and independently associated with hypertension-attributed nephropathy, with an adjusted odds ratio of 7.7 (95% confidence interval 1.5–39.7; P = 0.014). The high-risk APOL1 genotypes were G1/G1 and G1/G2, whereas G2/G2 was not found in the study population. Conclusions The results of this study demonstrate the association of high-risk APOL1 genotypes with kidney disease in Kinshasa. The absence of G2/G2 may be consistent with powerful selective sweeps induced by Trypanosoma brucei gambiense infection. In contrast, the presence of APOL1 G2/G2 among individuals of African ancestry in the USA may indicate relaxation of natural selection in a trypanosome-free environment.

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“…104,105 Sequencing studies in that gene region did not reveal other independent risk variants than G1 and G2. 106,107 ApoL1 is highly interesting from an evolutionary standpoint and is kind of a Trojan horse, causing human resistance against Trypanosoma brucei brucei. When HDL particles are taken up as nutrients by these parasites, the HDL-attached apoL1 is inserted in the membranes of the parasites and results in pore formation and lysis of the parasites.…”

Section: Apo L1mentioning

confidence: 99%

HDL in CKD—The Devil Is in the Detail

Kronenberg

2018

JASN

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The picture of HDL cholesterol (HDL-C) as the "good" cholesterol has eroded. This is even more surprising because there exists strong evidence that HDL-C is associated with cardiovascular disease (CVD) in the general population as well as in patients with impairment of kidney function and/or progression of CKD. However, drugs that dramatically increase HDL-C have mostly failed to decrease CVD events. Furthermore, genetic studies took the same line, as genetic variants that have a pronounced influence on HDL-C concentrations did not show an association with cardiovascular risk. For many, this was not surprising, given that an HDL particle is highly complex and carries >80 proteins and several hundred lipid species. Simply measuring cholesterol might not reflect the variety of biologic effects of heterogeneous HDL particles. Therefore, functional studies and the involvement of HDL components in the reverse cholesterol transport, including the cholesterol efflux capacity, have become a further focus of study during recent years. As also observed for other aspects, CKD populations behave differently compared with non-CKD populations. Although clear disturbances have been observed for the "functionality" of HDL particles in patients with CKD, this did not necessarily translate into clear-cut associations with outcomes.

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Re-Sequencing of the <b><i>APOL1</i></b>-<b><i>APOL4</i></b> and <b><i>MYH9</i></b> Gene Regions in African Americans Does Not Identify Additional Risks for CKD Progression

Cited by 13 publications

References 26 publications

Racial differences in microRNA and gene expression in hypertensive women

Racial differences in microRNA and gene expression in hypertensive women

G1 is the major APOL1 risk allele for hypertension-attributed nephropathy in Central Africa

HDL in CKD—The Devil Is in the Detail

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