TY - JOUR
T1 - Chromosome 2q31. 1 associates with ESRD in women with type 1 diabetes
AU - Sandholm, Niina
AU - McKnight, Amy Jayne
AU - Salem, Rany M.
AU - Brennan, Eoin P.
AU - Forsblom, Carol
AU - Harjutsalo, Valma
AU - Mäkinen, Ville Petteri
AU - McKay, Gareth J.
AU - Sadlier, Denise M.
AU - Williams, Winfred W.
AU - Martin, Finian
AU - Panduru, Nicolae Mircea
AU - Tarnow, Lise
AU - Tuomilehto, Jaakko
AU - Tryggvason, Karl
AU - Zerbini, Gianpaolo
AU - Comeau, Mary E.
AU - Langefeld, Carl D.
AU - Godson, Catherine
AU - Hirschhorn, Joel N.
AU - Maxwell, Alexander P.
AU - Florez, Jose C.
AU - Groop, Per Henrik
PY - 2013/10/1
Y1 - 2013/10/1
N2 - 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 a 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 estrogenresponsive 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.
AB - 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 a 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 estrogenresponsive 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.
UR - http://www.scopus.com/inward/record.url?scp=84885033741&partnerID=8YFLogxK
U2 - 10.1681/ASN.2012111122
DO - 10.1681/ASN.2012111122
M3 - Article
C2 - 24029427
AN - SCOPUS:84885033741
SN - 1046-6673
VL - 24
SP - 1537
EP - 1543
JO - Journal of the American Society of Nephrology : JASN
JF - Journal of the American Society of Nephrology : JASN
IS - 10
ER -