SNP in the genome-wide association study hotspot on chromosome 9p21 confers susceptibility to diabetic nephropathy in type 1 diabetes

Diabetologia. 2012 Sep;55(9):2386-93. doi: 10.1007/s00125-012-2587-0. Epub 2012 May 29.


Aims/hypothesis: Parental type 2 diabetes mellitus increases the risk of diabetic nephropathy in offspring with type 1 diabetes mellitus. Several single nucleotide polymorphisms (SNPs) that predispose to type 2 diabetes mellitus have recently been identified. It is, however, not known whether such SNPs also confer susceptibility to diabetic nephropathy in patients with type 1 diabetes mellitus.

Methods: We genotyped nine SNPs associated with type 2 diabetes mellitus in genome-wide association studies in the Finnish population, and tested for their association with diabetic nephropathy as well as with severe retinopathy and cardiovascular disease in 2,963 patients with type 1 diabetes mellitus. Replication of significant SNPs was sought in 2,980 patients from three other cohorts.

Results: In the discovery cohort, rs10811661 near gene CDKN2A/B was associated with diabetic nephropathy. The association remained after robust Bonferroni correction for the total number of tests performed in this study (OR 1.33 [95% CI 1.14, 1.56], p = 0.00045, p (36tests) = 0.016). In the meta-analysis, the combined result for diabetic nephropathy was significant, with a fixed effects p value of 0.011 (OR 1.15 [95% CI 1.02, 1.29]). The association was particularly strong when patients with end-stage renal disease were compared with controls (OR 1.35 [95% CI 1.13, 1.60], p = 0.00038). The same SNP was also associated with severe retinopathy (OR 1.37 [95% CI 1.10, 1.69] p = 0.0040), but the association did not remain after Bonferroni correction (p (36tests) = 0.14). None of the other selected SNPs was associated with nephropathy, severe retinopathy or cardiovascular disease.

Conclusions/interpretation: A SNP predisposing to type 2 diabetes mellitus, rs10811661 near CDKN2A/B, is associated with diabetic nephropathy in patients with type 1 diabetes mellitus.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Albuminuria / epidemiology
  • Albuminuria / genetics*
  • Chromosomes, Human, Pair 9*
  • Diabetes Mellitus, Type 1 / epidemiology
  • Diabetes Mellitus, Type 1 / genetics*
  • Diabetic Nephropathies / epidemiology
  • Diabetic Nephropathies / genetics*
  • Female
  • Finland / epidemiology
  • Genes, p16*
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study*
  • Humans
  • Kidney Diseases / epidemiology
  • Kidney Diseases / genetics*
  • Male
  • Middle Aged
  • Parents
  • Polymorphism, Single Nucleotide*
  • White People
  • Young Adult