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

Sudha K. Iyengar, John R. Sedor, Barry I. Freedman, W. H Linda Kao, Matthias Kretzler, Benjamin J. Keller, Hanna E. Abboud, Sharon G. Adler, Lyle G. Best, Donald W. Bowden, Allison Burlock, Yii Der Ida Chen, Shelley A. Cole, Mary E. Comeau, Jeffrey M. Curtis, Jasmin Divers, Christiane Drechsler, Ravi Duggirala, Robert C. Elston, Xiuqing GuoHuateng Huang, Michael Marcus Hoffmann, Barbara V. Howard, Eli Ipp, Paul L. Kimmel, Michael J. Klag, William C. Knowler, Orly F. Kohn, Tennille S. Leak, David J. Leehey, Man Li, Alka Malhotra, Winfried März, Viji Nair, Robert G. Nelson, Susanne B. Nicholas, Stephen J. O’Brien, Madeleine V. Pahl, Rulan S. Parekh, Marcus G. Pezzolesi, Rebekah S. Rasooly, Charles N. Rotimi, Jerome I. Rotter, Jeffrey R. Schelling, Michael F Seldin, Vallabh O. Shah, Adam M. Smiles, Michael W. Smith, Kent D. Taylor, Farook Thameem, Denyse P. Thornley-Brown, Barbara J. Truitt, Christoph Wanner, E. Jennifer Weil, Cheryl A. Winkler, Philip G. Zager, Robert P. Igo, Robert L. Hanson, Carl D. Langefeld

Research output: Contribution to journalArticle

51 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere1005352
JournalPLoS Genetics
Volume11
Issue number8
DOIs
StatePublished - Aug 1 2015

Fingerprint

diabetes
meta-analysis
Diabetic Nephropathies
kidney diseases
Meta-Analysis
genome
Genome
North American Indians
American Indians
African Americans
Single Nucleotide Polymorphism
Genome-Wide Association Study
Ethnic Groups
African American
ethnic group
nationalities and ethnic groups
family
Disease Susceptibility
Linkage Disequilibrium
Chronic Renal Insufficiency

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Iyengar, S. K., Sedor, J. R., Freedman, B. I., Kao, W. H. L., Kretzler, M., Keller, B. J., ... Langefeld, C. D. (2015). Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND). PLoS Genetics, 11(8), [e1005352]. https://doi.org/10.1371/journal.pgen.1005352

Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease : Family Investigation of Nephropathy and Diabetes (FIND). / Iyengar, Sudha K.; Sedor, John R.; Freedman, Barry I.; Kao, W. H Linda; Kretzler, Matthias; Keller, Benjamin J.; Abboud, Hanna E.; Adler, Sharon G.; Best, Lyle G.; Bowden, Donald W.; Burlock, Allison; Chen, Yii Der Ida; Cole, Shelley A.; Comeau, Mary E.; Curtis, Jeffrey M.; Divers, Jasmin; Drechsler, Christiane; Duggirala, Ravi; Elston, Robert C.; Guo, Xiuqing; Huang, Huateng; Hoffmann, Michael Marcus; Howard, Barbara V.; Ipp, Eli; Kimmel, Paul L.; Klag, Michael J.; Knowler, William C.; Kohn, Orly F.; Leak, Tennille S.; Leehey, David J.; Li, Man; Malhotra, Alka; März, Winfried; Nair, Viji; Nelson, Robert G.; Nicholas, Susanne B.; O’Brien, Stephen J.; Pahl, Madeleine V.; Parekh, Rulan S.; Pezzolesi, Marcus G.; Rasooly, Rebekah S.; Rotimi, Charles N.; Rotter, Jerome I.; Schelling, Jeffrey R.; Seldin, Michael F; Shah, Vallabh O.; Smiles, Adam M.; Smith, Michael W.; Taylor, Kent D.; Thameem, Farook; Thornley-Brown, Denyse P.; Truitt, Barbara J.; Wanner, Christoph; Weil, E. Jennifer; Winkler, Cheryl A.; Zager, Philip G.; Igo, Robert P.; Hanson, Robert L.; Langefeld, Carl D.

In: PLoS Genetics, Vol. 11, No. 8, e1005352, 01.08.2015.

Research output: Contribution to journalArticle

Iyengar, SK, Sedor, JR, Freedman, BI, Kao, WHL, Kretzler, M, Keller, BJ, Abboud, HE, Adler, SG, Best, LG, Bowden, DW, Burlock, A, Chen, YDI, 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 2015, 'Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND)', PLoS Genetics, vol. 11, no. 8, e1005352. https://doi.org/10.1371/journal.pgen.1005352
Iyengar, Sudha K. ; Sedor, John R. ; Freedman, Barry I. ; Kao, W. H Linda ; Kretzler, Matthias ; Keller, Benjamin J. ; Abboud, Hanna E. ; Adler, Sharon G. ; Best, Lyle G. ; Bowden, Donald W. ; Burlock, Allison ; Chen, Yii Der Ida ; Cole, Shelley A. ; Comeau, Mary E. ; Curtis, Jeffrey M. ; Divers, Jasmin ; Drechsler, Christiane ; Duggirala, Ravi ; Elston, Robert C. ; Guo, Xiuqing ; Huang, Huateng ; Hoffmann, Michael Marcus ; Howard, Barbara V. ; Ipp, Eli ; Kimmel, Paul L. ; Klag, Michael J. ; Knowler, William C. ; Kohn, Orly F. ; Leak, Tennille S. ; Leehey, David J. ; Li, Man ; Malhotra, Alka ; März, Winfried ; Nair, Viji ; Nelson, Robert G. ; Nicholas, Susanne B. ; O’Brien, Stephen J. ; Pahl, Madeleine V. ; Parekh, Rulan S. ; Pezzolesi, Marcus G. ; Rasooly, Rebekah S. ; Rotimi, Charles N. ; Rotter, Jerome I. ; Schelling, Jeffrey R. ; Seldin, Michael F ; Shah, Vallabh O. ; Smiles, Adam M. ; Smith, Michael W. ; Taylor, Kent D. ; Thameem, Farook ; Thornley-Brown, Denyse P. ; Truitt, Barbara J. ; Wanner, Christoph ; Weil, E. Jennifer ; Winkler, Cheryl A. ; Zager, Philip G. ; Igo, Robert P. ; Hanson, Robert L. ; Langefeld, Carl D. / Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease : Family Investigation of Nephropathy and Diabetes (FIND). In: PLoS Genetics. 2015 ; Vol. 11, No. 8.
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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.",
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T1 - Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease

T2 - Family Investigation of Nephropathy and Diabetes (FIND)

AU - Iyengar, Sudha K.

AU - Sedor, John R.

AU - Freedman, Barry I.

AU - Kao, W. H Linda

AU - Kretzler, Matthias

AU - Keller, Benjamin J.

AU - Abboud, Hanna E.

AU - Adler, Sharon G.

AU - Best, Lyle G.

AU - Bowden, Donald W.

AU - Burlock, Allison

AU - Chen, Yii Der Ida

AU - Cole, Shelley A.

AU - Comeau, Mary E.

AU - Curtis, Jeffrey M.

AU - Divers, Jasmin

AU - Drechsler, Christiane

AU - Duggirala, Ravi

AU - Elston, Robert C.

AU - Guo, Xiuqing

AU - Huang, Huateng

AU - Hoffmann, Michael Marcus

AU - Howard, Barbara V.

AU - Ipp, Eli

AU - Kimmel, Paul L.

AU - Klag, Michael J.

AU - Knowler, William C.

AU - Kohn, Orly F.

AU - Leak, Tennille S.

AU - Leehey, David J.

AU - Li, Man

AU - Malhotra, Alka

AU - März, Winfried

AU - Nair, Viji

AU - Nelson, Robert G.

AU - Nicholas, Susanne B.

AU - O’Brien, Stephen J.

AU - Pahl, Madeleine V.

AU - Parekh, Rulan S.

AU - Pezzolesi, Marcus G.

AU - Rasooly, Rebekah S.

AU - Rotimi, Charles N.

AU - Rotter, Jerome I.

AU - Schelling, Jeffrey R.

AU - Seldin, Michael F

AU - Shah, Vallabh O.

AU - Smiles, Adam M.

AU - Smith, Michael W.

AU - Taylor, Kent D.

AU - Thameem, Farook

AU - Thornley-Brown, Denyse P.

AU - Truitt, Barbara J.

AU - Wanner, Christoph

AU - Weil, E. Jennifer

AU - Winkler, Cheryl A.

AU - Zager, Philip G.

AU - Igo, Robert P.

AU - Hanson, Robert L.

AU - Langefeld, Carl D.

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AB - 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.

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