title: Chromosome 2q31.1 associates with ESRD in women with type 1 diabetes.
abstract: Sex and genetic variation influence the risk of developing diabetic nephropathy and ESRD in patients with type 1 diabetes. We performed a genome-wide association study in a cohort of 3652 patients from the Finnish Diabetic Nephropathy (FinnDiane) Study with type 1 diabetes to determine whether sex-specific genetic risk factors for ESRD exist. A common variant, rs4972593 on chromosome 2q31.1, was associated with ESRD in women (P<5×10(-8)) but not in men (P=0.77). This association was replicated in the meta-analysis of three independent type 1 diabetes cohorts (P=0.02) and remained significant for women (P<5×10(-8); odds ratio, 1.81 [95% confidence interval, 1.47 to 2.24]) upon combined meta-analysis of the discovery and replication cohorts. rs4972593 is located between the genes that code for the Sp3 transcription factor, which interacts directly with estrogen receptor α and regulates the expression of genes linked to glomerular function and the pathogenesis of nephropathy, and the CDCA7 transcription factor, which regulates cell proliferation. Further examination revealed potential transcription factor-binding sites within rs4972593 and predicted eight estrogen-responsive elements within 5 kb of this locus. Moreover, we found sex-specific differences in the glomerular expression levels of SP3 (P=0.004). Overall, these results suggest that rs4972593 is a sex-specific genetic variant associated with ESRD in patients with type 1 diabetes and may underlie the sex-specific protection against ESRD.
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland;
authors.forename: Niina
authors.initials: N
authors.lastname: Sandholm
authors.forename: Amy Jayne
authors.initials: AJ
authors.lastname: McKnight
authors.forename: Rany M
authors.initials: RM
authors.lastname: Salem
authors.forename: Eoin P
authors.initials: EP
authors.lastname: Brennan
authors.forename: Carol
authors.initials: C
authors.lastname: Forsblom
authors.forename: Valma
authors.initials: V
authors.lastname: Harjutsalo
authors.forename: Ville-Petteri
authors.initials: VP
authors.lastname: Mäkinen
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: McKay
authors.forename: Denise M
authors.initials: DM
authors.lastname: Sadlier
authors.forename: Winfred W
authors.initials: WW
authors.lastname: Williams
authors.forename: Finian
authors.initials: F
authors.lastname: Martin
authors.forename: Nicolae Mircea
authors.initials: NM
authors.lastname: Panduru
authors.forename: Lise
authors.initials: L
authors.lastname: Tarnow
authors.forename: Jaakko
authors.initials: J
authors.lastname: Tuomilehto
authors.forename: Karl
authors.initials: K
authors.lastname: Tryggvason
authors.forename: Gianpaolo
authors.initials: G
authors.lastname: Zerbini
authors.forename: Mary E
authors.initials: ME
authors.lastname: Comeau
authors.forename: Carl D
authors.initials: CD
authors.lastname: Langefeld
authors.forename: Catherine
authors.initials: C
authors.lastname: Godson
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
authors.forename: Alexander P
authors.initials: AP
authors.lastname: Maxwell
authors.forename: Jose C
authors.initials: JC
authors.lastname: Florez
authors.forename: Per-Henrik
authors.initials: PH
authors.lastname: Groop
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000150:complications*; D003928:Diabetic Nephropathies / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D007676:Kidney Failure, Chronic / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics; D012727:Sex Characteristics; D051705:Sp3 Transcription Factor / Q000235:genetics
chemical_list: C445325:CDCA7 protein, human; D009687:Nuclear Proteins; C497121:SP3 protein, human; D051705:Sp3 Transcription Factor
references.citation: Curr Diabetes Rev. 2011 Jan;7(1):28-34
references.pmid: 21067504
references.citation: PLoS Genet. 2012;8(4):e1002639
references.pmid: 22532805
references.citation: Diabetes. 2006 Nov;55(11):2993-3003
references.pmid: 17065335
references.citation: Cancer Res. 2005 Jul 1;65(13):5620-7
references.pmid: 15994934
references.citation: J Diabetes Complications. 2005 Jan-Feb;19(1):1-9
references.pmid: 15642484
references.citation: Diabetologia. 2011 Aug;54(8):1992-9
references.pmid: 21509443
references.citation: Gend Med. 2008;5 Suppl A:S3-S10
references.pmid: 18395681
references.citation: Biochim Biophys Acta. 2012 Apr;1822(4):589-99
references.pmid: 22266139
references.citation: Diabetes. 2004 Sep;53(9):2449-54
references.pmid: 15331558
references.citation: Diabetes Care. 1993 Oct;16(10):1376-83
references.pmid: 8269796
references.citation: Genome Res. 2012 Sep;22(9):1790-7
references.pmid: 22955989
references.citation: Bioinformatics. 2010 Sep 1;26(17):2190-1
references.pmid: 20616382
references.citation: J Biol Chem. 2012 Jan 27;287(5):3462-78
references.pmid: 22139845
references.citation: Gend Med. 2008;5 Suppl A:S103-13
references.pmid: 18395675
references.citation: J Biol Chem. 2000 Jul 28;275(30):22769-79
references.pmid: 10816575
references.citation: PLoS Genet. 2012 Sep;8(9):e1002921
references.pmid: 23028342
references.citation: Diabetes. 2011 Sep;60(9):2354-69
references.pmid: 21752957
references.citation: J Clin Invest. 2001 Dec;108(11):1621-9
references.pmid: 11733557
references.citation: Am J Pathol. 2001 Dec;159(6):2303-8
references.pmid: 11733379
references.citation: Bioinformatics. 2003 Jan;19(1):149-50
references.pmid: 12499305
references.citation: Am J Hum Genet. 2007 Sep;81(3):559-75
references.pmid: 17701901
references.citation: Nat Genet. 2006 Aug;38(8):904-9
references.pmid: 16862161
references.citation: Am J Cardiovasc Drugs. 2007;7(6):393-8
references.pmid: 18076206
references.citation: PLoS One. 2010 Apr 28;5(4):e10369
references.pmid: 20442780
references.citation: Diabetes Care. 2005 Aug;28(8):2019-24
references.pmid: 16043748
references.citation: Proc Natl Acad Sci U S A. 2008 May 13;105(19):6998-7003
references.pmid: 18458324
references.citation: Oncogene. 2004 Feb 5;23(5):1052-63
references.pmid: 14647449