Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND)
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. Independe...
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| creator | 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, Jr, Robert P Hanson, Robert L Langefeld, Carl D |
| description | 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. |
| doi_str_mv | 10.1371/journal.pgen.1005352 |
| format | Article |
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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.</description><identifier>ISSN: 1553-7404</identifier><identifier>ISSN: 1553-7390</identifier><identifier>EISSN: 1553-7404</identifier><identifier>DOI: 10.1371/journal.pgen.1005352</identifier><identifier>PMID: 26305897</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>African Americans - genetics ; Cancer ; Chronic kidney failure ; Complications and side effects ; Diabetes ; Diabetes Mellitus, Type 2 - complications ; Diabetes Mellitus, Type 2 - genetics ; Diabetic nephropathies ; Diabetic Nephropathies - ethnology ; Diabetic Nephropathies - genetics ; European Continental Ancestry Group - genetics ; Gene expression ; Genealogy ; Genetic aspects ; Genetic Predisposition to Disease ; Genome-wide association studies ; Genome-Wide Association Study ; Genomes ; Genomics ; Hispanic Americans - genetics ; Humans ; Indians, North American - genetics ; Kidney diseases ; Medical research ; Meta-analysis ; Mortality ; Native North Americans ; Public health ; RNA-Binding Proteins - genetics ; Studies ; United States</subject><ispartof>PLoS genetics, 2015-08, Vol.11 (8), p.e1005352-e1005352</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Iyengar SK, Sedor JR, Freedman BI, Kao WHL, Kretzler M, Keller BJ, et al. (2015) Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND). PLoS Genet 11(8): e1005352. doi:10.1371/journal.pgen.1005352</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c764t-269c136d13a90b5869dd2a44c0f32c358071c67ab915946134f5cd53ceb921ca3</citedby><cites>FETCH-LOGICAL-c764t-269c136d13a90b5869dd2a44c0f32c358071c67ab915946134f5cd53ceb921ca3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4549309/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4549309/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26305897$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Iyengar, Sudha K</creatorcontrib><creatorcontrib>Sedor, John R</creatorcontrib><creatorcontrib>Freedman, Barry I</creatorcontrib><creatorcontrib>Kao, W H Linda</creatorcontrib><creatorcontrib>Kretzler, Matthias</creatorcontrib><creatorcontrib>Keller, Benjamin J</creatorcontrib><creatorcontrib>Abboud, Hanna E</creatorcontrib><creatorcontrib>Adler, Sharon G</creatorcontrib><creatorcontrib>Best, Lyle G</creatorcontrib><creatorcontrib>Bowden, Donald W</creatorcontrib><creatorcontrib>Burlock, Allison</creatorcontrib><creatorcontrib>Chen, Yii-Der Ida</creatorcontrib><creatorcontrib>Cole, Shelley A</creatorcontrib><creatorcontrib>Comeau, Mary E</creatorcontrib><creatorcontrib>Curtis, Jeffrey M</creatorcontrib><creatorcontrib>Divers, Jasmin</creatorcontrib><creatorcontrib>Drechsler, Christiane</creatorcontrib><creatorcontrib>Duggirala, Ravi</creatorcontrib><creatorcontrib>Elston, Robert C</creatorcontrib><creatorcontrib>Guo, Xiuqing</creatorcontrib><creatorcontrib>Huang, Huateng</creatorcontrib><creatorcontrib>Hoffmann, Michael Marcus</creatorcontrib><creatorcontrib>Howard, Barbara V</creatorcontrib><creatorcontrib>Ipp, Eli</creatorcontrib><creatorcontrib>Kimmel, Paul L</creatorcontrib><creatorcontrib>Klag, Michael J</creatorcontrib><creatorcontrib>Knowler, William C</creatorcontrib><creatorcontrib>Kohn, Orly F</creatorcontrib><creatorcontrib>Leak, Tennille S</creatorcontrib><creatorcontrib>Leehey, David J</creatorcontrib><creatorcontrib>Li, Man</creatorcontrib><creatorcontrib>Malhotra, Alka</creatorcontrib><creatorcontrib>März, Winfried</creatorcontrib><creatorcontrib>Nair, Viji</creatorcontrib><creatorcontrib>Nelson, Robert G</creatorcontrib><creatorcontrib>Nicholas, Susanne B</creatorcontrib><creatorcontrib>O'Brien, Stephen J</creatorcontrib><creatorcontrib>Pahl, Madeleine V</creatorcontrib><creatorcontrib>Parekh, Rulan S</creatorcontrib><creatorcontrib>Pezzolesi, Marcus G</creatorcontrib><creatorcontrib>Rasooly, Rebekah S</creatorcontrib><creatorcontrib>Rotimi, Charles N</creatorcontrib><creatorcontrib>Rotter, Jerome I</creatorcontrib><creatorcontrib>Schelling, Jeffrey R</creatorcontrib><creatorcontrib>Seldin, Michael F</creatorcontrib><creatorcontrib>Shah, Vallabh O</creatorcontrib><creatorcontrib>Smiles, Adam M</creatorcontrib><creatorcontrib>Smith, Michael W</creatorcontrib><creatorcontrib>Taylor, Kent D</creatorcontrib><creatorcontrib>Thameem, Farook</creatorcontrib><creatorcontrib>Thornley-Brown, Denyse P</creatorcontrib><creatorcontrib>Truitt, Barbara J</creatorcontrib><creatorcontrib>Wanner, Christoph</creatorcontrib><creatorcontrib>Weil, E Jennifer</creatorcontrib><creatorcontrib>Winkler, Cheryl A</creatorcontrib><creatorcontrib>Zager, Philip G</creatorcontrib><creatorcontrib>Igo, Jr, Robert P</creatorcontrib><creatorcontrib>Hanson, Robert L</creatorcontrib><creatorcontrib>Langefeld, Carl D</creatorcontrib><creatorcontrib>Family Investigation of Nephropathy and Diabetes (FIND)</creatorcontrib><title>Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND)</title><title>PLoS genetics</title><addtitle>PLoS Genet</addtitle><description>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.</description><subject>African Americans - genetics</subject><subject>Cancer</subject><subject>Chronic kidney failure</subject><subject>Complications and side effects</subject><subject>Diabetes</subject><subject>Diabetes Mellitus, Type 2 - complications</subject><subject>Diabetes Mellitus, Type 2 - genetics</subject><subject>Diabetic nephropathies</subject><subject>Diabetic Nephropathies - ethnology</subject><subject>Diabetic Nephropathies - genetics</subject><subject>European Continental Ancestry Group - genetics</subject><subject>Gene expression</subject><subject>Genealogy</subject><subject>Genetic aspects</subject><subject>Genetic Predisposition to Disease</subject><subject>Genome-wide association studies</subject><subject>Genome-Wide Association Study</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Hispanic Americans - genetics</subject><subject>Humans</subject><subject>Indians, North American - genetics</subject><subject>Kidney diseases</subject><subject>Medical research</subject><subject>Meta-analysis</subject><subject>Mortality</subject><subject>Native North Americans</subject><subject>Public health</subject><subject>RNA-Binding Proteins - genetics</subject><subject>Studies</subject><subject>United States</subject><issn>1553-7404</issn><issn>1553-7390</issn><issn>1553-7404</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>DOA</sourceid><recordid>eNqVk9Fu0zAUQCMEYmPwBwgiIaHtIcWO7bjZA1K10VExOgkGPFqOfZO6SuwSpxX9Dz4YZ-2mRuIBlIc4zrnn2te-UfQSoxEmHL9bunVrZT1aVWBHGCFGWPooOsaMkYRTRB8fjI-iZ94vESJsnPOn0VGaEdQPj6PfV2BdA8kPoyGeeO-UkZ1xNpZWx7ettD6BbmGNij9DJ5NJyLj1xsela-OJ3kirQMeXRhbQBeaT0Ra24duD9HAeT2Vj6m08sxvwnal2ZlfGc1gtWreS3WJ7l2gnAB-fTmfzy7Pn0ZNS1h5e7N8n0bfph9uLj8n1zdXsYnKdKJ7RLkmzXGGSaUxkjgo2znKtU0mpQiVJVdgr4lhlXBY5ZjnNMKElU5oRBUWeYiXJSfR6513Vzot9Qb3APEUZpilPAzHbEdrJpVi1ppHtVjhpxN2Eaysh27DzGkSGSg6EI6Q1ozjl41xpWuR5wei4JGMeXO_32dZFA1qB7VpZD6TDP9YsROU2gjKaE5QHwele0Lqf61BR0RivoK6lBbfu1404YxlDfa43O7SSYWnGli4YVY-LCQ2uLNygnhr9hQqPhsYoZ6E0YX4QcDYICEwHv7pKrr0Xs69f_oOd_zt7833Ivj1gFyDrbuFdve7vlh-CdAeq1nnfQvlQaoxE30L3Jy76FhL7Fgphrw6P6SHovmfIH_voFVI</recordid><startdate>20150801</startdate><enddate>20150801</enddate><creator>Iyengar, 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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, Jr, Robert P ; Hanson, Robert L ; Langefeld, Carl D</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c764t-269c136d13a90b5869dd2a44c0f32c358071c67ab915946134f5cd53ceb921ca3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>African Americans - genetics</topic><topic>Cancer</topic><topic>Chronic kidney failure</topic><topic>Complications and side effects</topic><topic>Diabetes</topic><topic>Diabetes Mellitus, Type 2 - complications</topic><topic>Diabetes Mellitus, Type 2 - genetics</topic><topic>Diabetic nephropathies</topic><topic>Diabetic Nephropathies - ethnology</topic><topic>Diabetic Nephropathies - genetics</topic><topic>European Continental Ancestry Group - genetics</topic><topic>Gene expression</topic><topic>Genealogy</topic><topic>Genetic aspects</topic><topic>Genetic Predisposition to Disease</topic><topic>Genome-wide association studies</topic><topic>Genome-Wide Association Study</topic><topic>Genomes</topic><topic>Genomics</topic><topic>Hispanic Americans - genetics</topic><topic>Humans</topic><topic>Indians, North American - genetics</topic><topic>Kidney diseases</topic><topic>Medical research</topic><topic>Meta-analysis</topic><topic>Mortality</topic><topic>Native North Americans</topic><topic>Public health</topic><topic>RNA-Binding Proteins - genetics</topic><topic>Studies</topic><topic>United States</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Iyengar, Sudha K</creatorcontrib><creatorcontrib>Sedor, John R</creatorcontrib><creatorcontrib>Freedman, Barry I</creatorcontrib><creatorcontrib>Kao, W H Linda</creatorcontrib><creatorcontrib>Kretzler, Matthias</creatorcontrib><creatorcontrib>Keller, Benjamin J</creatorcontrib><creatorcontrib>Abboud, Hanna E</creatorcontrib><creatorcontrib>Adler, Sharon G</creatorcontrib><creatorcontrib>Best, Lyle G</creatorcontrib><creatorcontrib>Bowden, Donald W</creatorcontrib><creatorcontrib>Burlock, Allison</creatorcontrib><creatorcontrib>Chen, Yii-Der Ida</creatorcontrib><creatorcontrib>Cole, Shelley A</creatorcontrib><creatorcontrib>Comeau, Mary E</creatorcontrib><creatorcontrib>Curtis, Jeffrey M</creatorcontrib><creatorcontrib>Divers, Jasmin</creatorcontrib><creatorcontrib>Drechsler, Christiane</creatorcontrib><creatorcontrib>Duggirala, Ravi</creatorcontrib><creatorcontrib>Elston, Robert C</creatorcontrib><creatorcontrib>Guo, Xiuqing</creatorcontrib><creatorcontrib>Huang, Huateng</creatorcontrib><creatorcontrib>Hoffmann, Michael Marcus</creatorcontrib><creatorcontrib>Howard, Barbara V</creatorcontrib><creatorcontrib>Ipp, Eli</creatorcontrib><creatorcontrib>Kimmel, Paul L</creatorcontrib><creatorcontrib>Klag, Michael J</creatorcontrib><creatorcontrib>Knowler, William C</creatorcontrib><creatorcontrib>Kohn, Orly F</creatorcontrib><creatorcontrib>Leak, Tennille S</creatorcontrib><creatorcontrib>Leehey, David J</creatorcontrib><creatorcontrib>Li, Man</creatorcontrib><creatorcontrib>Malhotra, Alka</creatorcontrib><creatorcontrib>März, Winfried</creatorcontrib><creatorcontrib>Nair, Viji</creatorcontrib><creatorcontrib>Nelson, Robert G</creatorcontrib><creatorcontrib>Nicholas, Susanne B</creatorcontrib><creatorcontrib>O'Brien, Stephen J</creatorcontrib><creatorcontrib>Pahl, Madeleine V</creatorcontrib><creatorcontrib>Parekh, Rulan S</creatorcontrib><creatorcontrib>Pezzolesi, Marcus G</creatorcontrib><creatorcontrib>Rasooly, Rebekah S</creatorcontrib><creatorcontrib>Rotimi, Charles N</creatorcontrib><creatorcontrib>Rotter, Jerome I</creatorcontrib><creatorcontrib>Schelling, Jeffrey R</creatorcontrib><creatorcontrib>Seldin, Michael F</creatorcontrib><creatorcontrib>Shah, Vallabh O</creatorcontrib><creatorcontrib>Smiles, Adam M</creatorcontrib><creatorcontrib>Smith, Michael W</creatorcontrib><creatorcontrib>Taylor, Kent D</creatorcontrib><creatorcontrib>Thameem, Farook</creatorcontrib><creatorcontrib>Thornley-Brown, Denyse P</creatorcontrib><creatorcontrib>Truitt, Barbara J</creatorcontrib><creatorcontrib>Wanner, Christoph</creatorcontrib><creatorcontrib>Weil, E Jennifer</creatorcontrib><creatorcontrib>Winkler, Cheryl A</creatorcontrib><creatorcontrib>Zager, Philip G</creatorcontrib><creatorcontrib>Igo, Jr, Robert P</creatorcontrib><creatorcontrib>Hanson, Robert L</creatorcontrib><creatorcontrib>Langefeld, Carl D</creatorcontrib><creatorcontrib>Family Investigation of Nephropathy and Diabetes (FIND)</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Canada</collection><collection>Gale In Context: Science</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PLoS genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Iyengar, Sudha K</au><au>Sedor, John R</au><au>Freedman, Barry I</au><au>Kao, W H Linda</au><au>Kretzler, Matthias</au><au>Keller, Benjamin J</au><au>Abboud, Hanna E</au><au>Adler, Sharon G</au><au>Best, Lyle G</au><au>Bowden, Donald W</au><au>Burlock, Allison</au><au>Chen, Yii-Der Ida</au><au>Cole, Shelley A</au><au>Comeau, Mary E</au><au>Curtis, Jeffrey M</au><au>Divers, Jasmin</au><au>Drechsler, Christiane</au><au>Duggirala, Ravi</au><au>Elston, Robert C</au><au>Guo, Xiuqing</au><au>Huang, Huateng</au><au>Hoffmann, Michael Marcus</au><au>Howard, Barbara V</au><au>Ipp, Eli</au><au>Kimmel, Paul L</au><au>Klag, Michael J</au><au>Knowler, William C</au><au>Kohn, Orly F</au><au>Leak, Tennille S</au><au>Leehey, David J</au><au>Li, Man</au><au>Malhotra, Alka</au><au>März, Winfried</au><au>Nair, Viji</au><au>Nelson, Robert G</au><au>Nicholas, Susanne B</au><au>O'Brien, Stephen J</au><au>Pahl, Madeleine V</au><au>Parekh, Rulan S</au><au>Pezzolesi, Marcus G</au><au>Rasooly, Rebekah S</au><au>Rotimi, Charles N</au><au>Rotter, Jerome I</au><au>Schelling, Jeffrey R</au><au>Seldin, Michael F</au><au>Shah, Vallabh O</au><au>Smiles, Adam M</au><au>Smith, Michael W</au><au>Taylor, Kent D</au><au>Thameem, Farook</au><au>Thornley-Brown, Denyse P</au><au>Truitt, Barbara J</au><au>Wanner, Christoph</au><au>Weil, E Jennifer</au><au>Winkler, Cheryl A</au><au>Zager, Philip G</au><au>Igo, Jr, Robert P</au><au>Hanson, Robert L</au><au>Langefeld, Carl D</au><aucorp>Family Investigation of Nephropathy and Diabetes (FIND)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND)</atitle><jtitle>PLoS genetics</jtitle><addtitle>PLoS Genet</addtitle><date>2015-08-01</date><risdate>2015</risdate><volume>11</volume><issue>8</issue><spage>e1005352</spage><epage>e1005352</epage><pages>e1005352-e1005352</pages><issn>1553-7404</issn><issn>1553-7390</issn><eissn>1553-7404</eissn><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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26305897</pmid><doi>10.1371/journal.pgen.1005352</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1553-7404 |
| ispartof | PLoS genetics, 2015-08, Vol.11 (8), p.e1005352-e1005352 |
| issn | 1553-7404 1553-7390 1553-7404 |
| language | eng |
| recordid | cdi_plos_journals_1720614272 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Public Library of Science (PLoS) |
| subjects | African Americans - genetics Cancer Chronic kidney failure Complications and side effects Diabetes Diabetes Mellitus, Type 2 - complications Diabetes Mellitus, Type 2 - genetics Diabetic nephropathies Diabetic Nephropathies - ethnology Diabetic Nephropathies - genetics European Continental Ancestry Group - genetics Gene expression Genealogy Genetic aspects Genetic Predisposition to Disease Genome-wide association studies Genome-Wide Association Study Genomes Genomics Hispanic Americans - genetics Humans Indians, North American - genetics Kidney diseases Medical research Meta-analysis Mortality Native North Americans Public health RNA-Binding Proteins - genetics Studies United States |
| title | Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND) |
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