New Susceptibility Loci Associated with Kidney Disease in Type 1 Diabetes

被引：202

作者：

Sandholm, Niina ^{[1
,2
,3
]}

Salem, Rany M. ^{[4
,5
,6
]}

McKnight, Amy Jayne ^{[7
]}

Brennan, Eoin P. ^{[8
,9
]}

Forsblom, Carol ^{[1
,2
]}

Isakova, Tamara ^{[10
]}

McKay, Gareth J. ^{[7
]}

Williams, Winfred W. ^{[6
,11
]}

Sadlier, Denise M. ^{[8
,9
]}

Makinen, Ville-Petteri ^{[1
,2
,12
,13
]}

Swan, Elizabeth J. ^{[7
]}

Palmer, Cameron ^{[4
,5
]}

Boright, Andrew P. ^{[14
]}

Ahlqvist, Emma ^{[15
]}

Deshmukh, Harshal A. ^{[16
]}

Keller, Benjamin J. ^{[17
]}

Huang, Huateng ^{[18
]}

Ahola, Aila J. ^{[1
,2
]}

Fagerholm, Emma ^{[1
,2
]}

Gordin, Daniel ^{[1
,2
]}

Harjutsalo, Valma ^{[1
,2
,19
]}

He, Bing ^{[20
]}

Heikkila, Outi ^{[1
,2
]}

Hietala, Kustaa ^{[1
,21
]}

Kyto, Janne ^{[1
,21
]}

Lahermo, Paivi ^{[22
]}

Lehto, Markku ^{[1
,2
]}

Lithovius, Raija ^{[1
,2
]}

Osterholm, Anne-May ^{[20
]}

Parkkonen, Maija ^{[1
,2
]}

Pitkaniemi, Janne ^{[23
]}

Rosengard-Barlund, Milla ^{[1
,2
]}

Saraheimo, Markku ^{[1
,2
]}

Sarti, Cinzia ^{[23
]}

Soderlund, Jenny ^{[1
,2
]}

Soro-Paavonen, Aino ^{[1
,2
]}

Syreeni, Anna ^{[1
,2
]}

Thorn, Lena M. ^{[1
,2
]}

Tikkanen, Heikki ^{[24
]}

Tolonen, Nina ^{[1
,2
]}

Tryggvason, Karl ^{[20
]}

Tuomilehto, Jaakko ^{[19
,25
,26
,27
]}

Waden, Johan ^{[1
,2
]}

Gill, Geoffrey V. ^{[28
]}

Prior, Sarah ^{[29
]}

Guiducci, Candace ^{[4
]}

Mirel, Daniel B. ^{[4
]}

Taylor, Andrew ^{[4
,11
]}

Hosseini, S. Mohsen ^{[30
,31
]}

Parving, Hans-Henrik ^{[33
,34
]}

机构：

[1] Biomedicum Helsinki, Folkhalsan Res Ctr, Folkhalsan Inst Genet, Helsinki, Finland

[2] Univ Helsinki, Cent Hosp, Dept Med, Div Nephrol, Helsinki, Finland

[3] Aalto Univ, Dept Biomed Engn & Computat Sci, Espoo, Finland

[4] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA

[5] Childrens Hosp, Dept Endocrinol, Endocrine Res Unit, Boston, MA 02115 USA

[6] Harvard Univ, Sch Med, Dept Med, Cambridge, MA 02138 USA

[7] Queens Univ Belfast, Ctr Publ Hlth, Nephrol Res, Belfast, North Ireland

[8] Univ Coll Dublin, Sch Med & Med Sci, Conway Inst, Diabet Res Ctr, Dublin, Ireland

[9] Mater Misericordiae Univ Hosp, Dublin, Ireland

[10] Univ Miami, Div Nephrol & Hypertens, Miami, FL USA

[11] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[12] Univ Oulu, Bioctr Oulu, Dept Internal Med, Inst Clin Med, Oulu, Finland

[13] Univ Oulu, Clin Res Ctr, Oulu, Finland

[14] Univ Toronto, Dept Med, Toronto, ON, Canada

[15] Lund Univ, Skane Univ Hosp, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden

[16] Univ Dundee, Wellcome Trust Ctr Mol Med, Dundee, Scotland

[17] Eastern Michigan Univ, Comp Sci, Ypsilanti, MI USA

[18] Univ Michigan, Div Nephrol, Internal Med, Ann Arbor, MI USA

[19] Natl Inst Hlth & Welf, Diabet Prevent Unit, Helsinki, Finland

[20] Karolinska Inst, Dept Med Biochem & Biophys, Div Matrix Biol, Stockholm, Sweden

[21] Univ Helsinki, Cent Hosp, Dept Ophthalmol, Helsinki, Finland

[22] Inst Mol Med Finland, Helsinki, Finland

[23] Univ Helsinki, Dept Publ Hlth, Hjelt Inst, Helsinki, Finland

[24] Univ Helsinki, Inst Clin Med, Unit Sports & Exercise Med, Helsinki, Finland

[25] South Ostrobothnia Cent Hosp, Seinajoki, Finland

[26] Hosp Univ La Paz, Red RECAVA Grp RD06 0014 0015, Madrid, Spain

[27] Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria

[28] Univ Liverpool, Aintree Univ Hosp, Diabet Endocrine Unit, Ctr Clin Sci, Liverpool, England

[29] Swansea Univ, Inst Life Sci, Swansea, Wales

[30] Univ Toronto, Inst Med Sci, Toronto, ON, Canada

[31] Hosp Sick Children, Program Genet & Genome Biol, Toronto, ON, Canada

[32] George Washington Univ, Biostat Div, Washington, DC USA

[33] Univ Copenhagen Hosp, Dept Med Endocrinol, Copenhagen, Denmark

[34] Univ Aarhus, Fac Hlth Sci, Aarhus, Denmark

[35] Steno Diabet Ctr, Gentofte, Denmark

[36] Pierre & Marie Curie Univ, Paris Descartes Univ, INSERM, U872, Paris, France

[37] CHU Sart Tilman, Liege, Belgium

[38] CHU Bordeaux, Bordeaux, France

[39] Hop Bichat Claude Bernard, AP HP, Diabetol Endocrinol Nutr, Paris, France

[40] Univ Paris Diderot, UMR 738, Sorbonne Paris Cite, Paris, France

[41] INSERM, Ctr Rech Cordeliers, Equipe 2, UMR872, Paris, France

[42] Pierre & Marie Curie Univ, ICAN Inst Cardiometab & Nutr, INSERM, UMR S 937, Paris, France

[43] Ist Sci San Raffaele, Complicat Diabet Unit, Div Metab & Cardiovasc Sci, Milan, Italy

[44] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden

[45] Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, Stockholm, Sweden

[46] Umea Univ, Dept Clin Sci, Paediat, Umea, Sweden

[47] Univ Bucharest, Genet Dept, Bucharest, Romania

[48] Univ Med & Pharm Craiova, Craiova, Romania

[49] Carol Davila Univ Med & Pharm, Bucharest, Romania

[50] NIDDK, Diabet Epidemiol & Clin Res Sect, Phoenix, AZ USA

来源：

PLOS GENETICS | 2012年 / 8卷 / 09期

基金：

英国医学研究理事会; 爱尔兰科学基金会; 美国国家卫生研究院;

关键词：

GENOME-WIDE ASSOCIATION; NATURAL-HISTORY; COLLAGEN CHAINS; AF4/FMR2; FAMILY; RENAL-FUNCTION; GROWTH-FACTOR; EXPRESSION; NEPHROPATHY; RISK; GENE;

D O I：

10.1371/journal.pgen.1002921

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genomewide association studies (GWAS) of T1D DN comprising similar to 2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2 x 10(-8)) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0 x 10(-9)). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-beta 1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1 x 10(-7)), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.

引用

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