TY - JOUR
T1 - SNP in the genome-wide association study hotspot on chromosome 9p21 confers susceptibility to diabetic nephropathy in type 1 diabetes
AU - Fagerholm, E.
AU - Ahlqvist, E.
AU - Forsblom, C.
AU - Sandholm, N.
AU - Syreeni, A.
AU - Parkkonen, M.
AU - McKnight, A. J.
AU - Tarnow, L.
AU - Maxwell, A. P.
AU - Parving, H. H.
AU - Groop, L.
AU - Groop, P. H.
PY - 2012/9/1
Y1 - 2012/9/1
N2 - 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.
AB - 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.
KW - CDKN2A
KW - Diabetic nephropathy
KW - Genetics
KW - rs10811661
KW - Type 1 diabetes mellitus
KW - Type 2 diabetes mellitus
UR - http://www.scopus.com/inward/record.url?scp=84866130556&partnerID=8YFLogxK
U2 - 10.1007/s00125-012-2587-0
DO - 10.1007/s00125-012-2587-0
M3 - Article
C2 - 22643932
AN - SCOPUS:84866130556
SN - 0012-186X
VL - 55
SP - 2386
EP - 2393
JO - Diabetologia
JF - Diabetologia
IS - 9
ER -