SNP in the genome-wide association study hotspot on chromosome 9p21 confers susceptibility to diabetic nephropathy in type 1 diabetes.
OBJECTIVE
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
A SNP predisposing to type 2 diabetes mellitus, rs10811661 near CDKN2A/B, is associated with diabetic nephropathy in patients with type 1 diabetes mellitus.
Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, University of Helsinki, Haartmaninkatu 8, POB 63, 00014 Helsinki, Finland.
E
E
Fagerholm
E
E
Ahlqvist
C
C
Forsblom
N
N
Sandholm
A
A
Syreeni
M
M
Parkkonen
A J
AJ
McKnight
L
L
Tarnow
A P
AP
Maxwell
H-H
HH
Parving
L
L
Groop
P-H
PH
Groop
D000328:Adult; D000419:Albuminuria / Q000453:epidemiology / Q000235:genetics*; D002899:Chromosomes, Human, Pair 9; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology / Q000235:genetics*; D003928:Diabetic Nephropathies / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D005387:Finland / Q000453:epidemiology; D019942:Genes, p16; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007674:Kidney Diseases / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010290:Parents; D020641:Polymorphism, Single Nucleotide; D044465:White People; D055815:Young Adult