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

被引：111

作者：

Iyengar, Sudha K. ^{[1
]}

Sedor, John R. ^{[2
,3
]}

Freedman, Barry I. ^{[4
]}

Kao, W. H. Linda ^{[5
]}

Kretzler, Matthias ^{[6
]}

Keller, Benjamin J. ^{[6
]}

Abboud, Hanna E. ^{[7
]}

Adler, Sharon G. ^{[8
]}

Best, Lyle G. ^{[9
]}

Bowden, Donald W. ^{[10
]}

Burlock, Allison

Chen, Yii-Der Ida ^{[11
]}

Cole, Shelley A. ^{[12
]}

Comeau, Mary E. ^{[13
,14
]}

Curtis, Jeffrey M. ^{[15
]}

Divers, Jasmin ^{[13
,14
]}

Drechsler, Christiane ^{[16
,17
]}

Duggirala, Ravi ^{[12
]}

Elston, Robert C. ^{[1
]}

Guo, Xiuqing ^{[11
]}

Huang, Huateng ^{[18
]}

Hoffmann, Michael Marcus ^{[19
]}

Howard, Barbara V. ^{[20
]}

Ipp, Eli ^{[21
]}

Kimmel, Paul L. ^{[22
]}

Klag, Michael J. ^{[23
]}

Knowler, William C. ^{[15
]}

Kohn, Orly F. ^{[24
]}

Leak, Tennille S. ^{[6
]}

Leehey, David J. ^{[25
]}

Li, Man ^{[26
]}

Malhotra, Alka ^{[15
]}

Maerz, Winfried ^{[27
,28
]}

Nair, Viji ^{[6
]}

Nelson, Robert G. ^{[15
]}

Nicholas, Susanne B. ^{[29
]}

O'Brien, Stephen J. ^{[30
,31
]}

Pahl, Madeleine V. ^{[32
]}

Parekh, Rulan S. ^{[33
,34
]}

Pezzolesi, Marcus G. ^{[35
]}

Rasooly, Rebekah S. ^{[36
]}

Rotimi, Charles N. ^{[37
]}

Rotter, Jerome I. ^{[11
]}

Schelling, Jeffrey R. ^{[2
]}

Seldin, Michael F. ^{[38
]}

Shah, Vallabh O. ^{[39
]}

Smiles, Adam M. ^{[40
]}

Smith, Michael W. ^{[41
]}

Taylor, Kent D. ^{[11
]}

Thameem, Farook ^{[42
]}

机构：

[1] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA

[2] Case Western Reserve Univ, Dept Med, Cleveland, OH 44106 USA

[3] Case Western Reserve Univ, Dept Physiol & Biophys, Cleveland, OH 44106 USA

[4] Wake Forest Sch Med, Dept Internal Med, Nephrol Sect, Winston Salem, NC USA

[5] Johns Hopkins Univ, Dept Epidemiol & Med, Baltimore, MD USA

[6] Univ Michigan, Dept Internal Med Nephrol, Ann Arbor, MI 48109 USA

[7] Univ Texas Hlth Sci Ctr San Antonio, Dept Med Nephrol, San Antonio, TX USA

[8] Harbor UCLA Med Ctr, Dept Med, Div Nephrol & Hypertens, Torrance, CA 90509 USA

[9] Missouri Breaks Ind Res, Timber Lake, SD USA

[10] Wake Forest Sch Med, Ctr Human Gen, Dept Biochem, Winston Salem, NC USA

[11] Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA

[12] Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA

[13] Wake Forest Sch Med, Ctr Publ Hlth Genom, Winston Salem, NC USA

[14] Wake Forest Sch Med, Dept Biostat Sci, Div Publ Hlth Sci, Winston Salem, NC USA

[15] NIDDK, NIH, Phoenix, AZ USA

[16] Univ Hosp Wurzburg, Div Renal, Wurzburg, Germany

[17] Univ Hosp Wurzburg, Comprehens Heart Failure Ctr, Wurzburg, Germany

[18] Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA

[19] Univ Med Ctr, Dept Clin Chem, Freiburg, Germany

[20] MedStar Hlth Res Inst, Hyattsville, MD USA

[21] Harbor UCLA Med Ctr, Dept Med, Sect Diabet & Metab, Torrance, CA 90509 USA

[22] NIDDK, Div Kidney Urol & Hematol Dis, Bethesda, MD 20892 USA

[23] Johns Hopkins Sch Med, Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA

[24] Univ Chicago Med, Dept Med, Chicago, IL USA

[25] Loyola Sch Med, Dept Med, Maywood, IL USA

[26] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA

[27] Heidelberg Univ, Graz, Austria

[28] Graz Univ, Synlab Acad, Graz, Austria

[29] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA

[30] Theodosius Dobzhansky Ctr Genome Bioinformat, St Petersburg, Russia

[31] Nova SE Univ, Oceanog Ctr, Ft Lauderdale, FL 33314 USA

[32] Univ Calif Irvine, Dept Med, Irvine, CA 92717 USA

[33] Univ Hlth Network, Hosp Sick Children, Dept Paediat & Med, Toronto, ON, Canada

[34] Univ Toronto, Toronto, ON, Canada

[35] Harvard Univ, Sch Med, Joslin Diabet Ctr, Dept Med, Boston, MA 02115 USA

[36] Natl Inst Diabet & Digest Dis, NIH, Bethesda, MD USA

[37] Ctr Res Genom & Global Hlth, Bethesda, MD USA

[38] Univ Calif Davis, Sch Med, Dept Biochem & Mol Med, Davis, CA USA

[39] Univ New Mexico, Dept Biochem & Mol Biol, Albuquerque, NM 87131 USA

[40] Joslin Diabet Ctr, Sect Genet & Epidemiol, Boston, MA 02215 USA

[41] NHGRI, Rockville, MD USA

[42] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA

[43] Univ Alabama Birmingham, Nephrol, Birmingham, AL USA

[44] Univ Hosp Wurzburg, Div Nephrol, Dept Med, Wurzburg, Germany

[45] NCI, Ctr Canc Res, Frederick, MD 21701 USA

[46] Univ New Mexico, Dept Internal Med, Albuquerque, NM 87131 USA

来源：

PLOS GENETICS | 2015年 / 11卷 / 08期

基金：

美国国家卫生研究院;

关键词：

STAGE RENAL-DISEASE; GLOMERULAR-FILTRATION-RATE; PROTEIN; TYPE-1; LOCI; ALBUMINURIA; EXPRESSION; RECEPTOR; MYH9; SUSCEPTIBILITY;

D O I：

10.1371/journal.pgen.1005352

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页数：19

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