학술논문
Chromosome 2q31.1 associates with ESRD in women with type 1 diabetes.
Document Type
Academic Journal
Author
Sandholm, Niina; McKnight, Amy Jayne; Salem, Rany M; Brennan, Eoin P; Forsblom, Carol; Harjutsalo, Valma; Mäkinen, Ville-Petteri; McKay, Gareth J; Sadlier, Denise M; Williams, Winfred W; Martin, Finian; Panduru, Nicolae Mircea; Tarnow, Lise; Tuomilehto, Jaakko; Tryggvason, Karl; Zerbini, Gianpaolo; Comeau, Mary E; Langefeld, Carl D; Godson, Catherine; Hirschhorn, Joel N; et al
Source
Subject
Language
English
ISSN
1046-6673
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.