Chromosome 2q31.1 associates with ESRD in women with type 1 diabetes

J Am Soc Nephrol. 2013 Oct;24(10):1537-43. doi: 10.1681/ASN.2012111122. Epub 2013 Sep 12.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Case-Control Studies
  • Chromosomes, Human, Pair 2 / genetics*
  • Diabetes Mellitus, Type 1 / complications*
  • Diabetic Nephropathies / genetics*
  • Female
  • Genome-Wide Association Study
  • Humans
  • Kidney Failure, Chronic / genetics*
  • Male
  • Middle Aged
  • Nuclear Proteins / genetics
  • Sex Characteristics
  • Sp3 Transcription Factor / genetics


  • CDCA7 protein, human
  • Nuclear Proteins
  • SP3 protein, human
  • Sp3 Transcription Factor

Grant support