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Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND).

Iyengar SK, Sedor JR, Freedman BI, Kao WH, Kretzler M, Keller BJ, Abboud HE, Adler SG, Best LG, Bowden DW, Burlock A, Chen YD, Cole SA, Comeau ME, Curtis JM, Divers J, Drechsler C, Duggirala R, Elston RC, Guo X, Huang H, Hoffmann MM, Howard BV, Ipp E, Kimmel PL, Klag MJ, Knowler WC, Kohn OF, Leak TS, Leehey DJ, Li M, Malhotra A, März W, Nair V, Nelson RG, Nicholas SB, O'Brien SJ, Pahl MV, Parekh RS, Pezzolesi MG, Rasooly RS, Rotimi CN, Rotter JI, Schelling JR, Seldin MF, Shah VO, Smiles AM, Smith MW, Taylor KD, Thameem F, Thornley-Brown DP, Truitt BJ, Wanner C, Weil EJ, Winkler CA, Zager PG, Igo RP, Hanson RL, Langefeld CD, Family Investigation of Nephropathy and Diabetes (FIN - PLoS Genet. (2015)

Bottom Line: Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10-9).The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10-8), with directionally consistent results across ethnic groups.These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD.

View Article: PubMed Central - PubMed

Affiliation: Department of Epidemiology & Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States of America.

ABSTRACT
Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10-9). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10-8), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD.

No MeSH data available.


Related in: MedlinePlus

Manhattan plot of FIND GWAS meta-analysis associations across ancestries included in Discovery and Replication samples.
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pgen.1005352.g001: Manhattan plot of FIND GWAS meta-analysis associations across ancestries included in Discovery and Replication samples.

Mentions: The only locus that reached genome wide significance for DKD in the trans-ethnic meta-analysis encompassing all FIND Discovery and Replication samples was rs955333 on chromosome 6 (minimum p-value 1.31x10-8 [additive]; minimum p-value 9.02x10-11 [dominant]) (Table 2). Fig 1 contains the Manhattan plot for the meta-analysis across all ancestries included in the Discovery and Replication samples. Consistent directions of association were present in three ethnic groups (only AA samples did not pass QC) and several supporting single nucleotide polymorphisms (SNPs) were detected in the region (regional plot in Fig 2). This SNP lies between the SR-like carboxyl-terminal domain associated factor 8 gene (SCAF8) and the connector enhancer of KSR family of scaffold proteins gene (CNKSR3), suggesting a possible role in transcription regulation. CNKSR3 is a direct mineralocorticoid receptor target gene involved in regulation of the epithelial sodium channel (ENaC) on the apical membrane of cells in the distal nephron.[12] CNKSR3 is highly expressed in the renal cortical collecting duct and upregulated in response to physiologic aldosterone concentrations. ENaC precisely regulates renal sodium absorption and plays important roles in maintenance of plasma volume and blood pressure. Ziera et al. [12] suggested that CNKSR3, a PSD-95/DLG-1/ZO-1 (PDZ) domain containing protein, inhibits the RAS/ERK signaling pathway, stimulating ENaC activity with enhanced renal sodium absorption. More recently, CNKSR3 was shown to function as an aldosterone-induced scaffolding platform that orchestrated assembly of ENaC and its regulators Nedd4-2, Raf-1 and SGK-1 and was essential for stimulation of ENaC function by aldosterone.[13] Clinically, renin-angiotensin-aldosterone system (RAAS) blockade serves as a mainstay of therapy for patients with DKD and other proteinuric kidney diseases.[14,15] Inhibition of aldosterone may further limit renal fibrosis, independent of natriuretic effects.[16,17] Hence, significant association between DKD and markers near CNKSR3 is consistent with clinical trial data demonstrating that blockade of the renin angiotensin system or the aldosterone receptor slows DKD progression. However, further experiments are needed to demonstrate that the associated SNP regulates the pathogenesis of progressive DKD. Further studies will be necessary to assess if the CNKSR3 regulates DKD pathogenesis indirectly by its effects on ENaC activity or directly by promoting aldosterone-dependent fibrosis.


Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND).

Iyengar SK, Sedor JR, Freedman BI, Kao WH, Kretzler M, Keller BJ, Abboud HE, Adler SG, Best LG, Bowden DW, Burlock A, Chen YD, Cole SA, Comeau ME, Curtis JM, Divers J, Drechsler C, Duggirala R, Elston RC, Guo X, Huang H, Hoffmann MM, Howard BV, Ipp E, Kimmel PL, Klag MJ, Knowler WC, Kohn OF, Leak TS, Leehey DJ, Li M, Malhotra A, März W, Nair V, Nelson RG, Nicholas SB, O'Brien SJ, Pahl MV, Parekh RS, Pezzolesi MG, Rasooly RS, Rotimi CN, Rotter JI, Schelling JR, Seldin MF, Shah VO, Smiles AM, Smith MW, Taylor KD, Thameem F, Thornley-Brown DP, Truitt BJ, Wanner C, Weil EJ, Winkler CA, Zager PG, Igo RP, Hanson RL, Langefeld CD, Family Investigation of Nephropathy and Diabetes (FIN - PLoS Genet. (2015)

Manhattan plot of FIND GWAS meta-analysis associations across ancestries included in Discovery and Replication samples.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4549309&req=5

pgen.1005352.g001: Manhattan plot of FIND GWAS meta-analysis associations across ancestries included in Discovery and Replication samples.
Mentions: The only locus that reached genome wide significance for DKD in the trans-ethnic meta-analysis encompassing all FIND Discovery and Replication samples was rs955333 on chromosome 6 (minimum p-value 1.31x10-8 [additive]; minimum p-value 9.02x10-11 [dominant]) (Table 2). Fig 1 contains the Manhattan plot for the meta-analysis across all ancestries included in the Discovery and Replication samples. Consistent directions of association were present in three ethnic groups (only AA samples did not pass QC) and several supporting single nucleotide polymorphisms (SNPs) were detected in the region (regional plot in Fig 2). This SNP lies between the SR-like carboxyl-terminal domain associated factor 8 gene (SCAF8) and the connector enhancer of KSR family of scaffold proteins gene (CNKSR3), suggesting a possible role in transcription regulation. CNKSR3 is a direct mineralocorticoid receptor target gene involved in regulation of the epithelial sodium channel (ENaC) on the apical membrane of cells in the distal nephron.[12] CNKSR3 is highly expressed in the renal cortical collecting duct and upregulated in response to physiologic aldosterone concentrations. ENaC precisely regulates renal sodium absorption and plays important roles in maintenance of plasma volume and blood pressure. Ziera et al. [12] suggested that CNKSR3, a PSD-95/DLG-1/ZO-1 (PDZ) domain containing protein, inhibits the RAS/ERK signaling pathway, stimulating ENaC activity with enhanced renal sodium absorption. More recently, CNKSR3 was shown to function as an aldosterone-induced scaffolding platform that orchestrated assembly of ENaC and its regulators Nedd4-2, Raf-1 and SGK-1 and was essential for stimulation of ENaC function by aldosterone.[13] Clinically, renin-angiotensin-aldosterone system (RAAS) blockade serves as a mainstay of therapy for patients with DKD and other proteinuric kidney diseases.[14,15] Inhibition of aldosterone may further limit renal fibrosis, independent of natriuretic effects.[16,17] Hence, significant association between DKD and markers near CNKSR3 is consistent with clinical trial data demonstrating that blockade of the renin angiotensin system or the aldosterone receptor slows DKD progression. However, further experiments are needed to demonstrate that the associated SNP regulates the pathogenesis of progressive DKD. Further studies will be necessary to assess if the CNKSR3 regulates DKD pathogenesis indirectly by its effects on ENaC activity or directly by promoting aldosterone-dependent fibrosis.

Bottom Line: Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10-9).The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10-8), with directionally consistent results across ethnic groups.These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD.

View Article: PubMed Central - PubMed

Affiliation: Department of Epidemiology & Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States of America.

ABSTRACT
Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10-9). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10-8), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD.

No MeSH data available.


Related in: MedlinePlus