Genetic Examination of SETD7 and SUV39H1/H2 Methyltransferases and the Risk of Diabetes Complications in Patients With Type 1 Diabetes
- Anna Syreeni1,
- Assam El-Osta2,
- Carol Forsblom1,3,
- Niina Sandholm1,
- Maikki Parkkonen1,
- Lise Tarnow4,
- Hans-Henrik Parving5,
- Amy J. McKnight6,
- Alexander P. Maxwell6,
- Mark E. Cooper2,
- Per-Henrik Groop1,2,3⇓ and
- on behalf of the FinnDiane Study Group
- 1Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland
- 2Epigenetics in Human Health and Disease Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
- 3Department of Medicine, Division of Nephrology, Helsinki University Central Hospital, Helsinki, Finland
- 4Steno Diabetes Center, Gentofte, Denmark
- 5Department of Medical Endocrinology, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark
- 6Nephrology Research Group, Queen’s University of Belfast, Belfast, Northern Ireland, U.K.
- Corresponding author: Per-Henrik Groop, .
OBJECTIVE Hyperglycemia plays a pivotal role in the development and progression of vascular complications, which are the major sources of morbidity and mortality in diabetes. Furthermore, these vascular complications often persist and progress despite improved glucose control, possibly as a result of prior episodes of hyperglycemia. Epigenetic modifications mediated by histone methyltransferases are associated with gene-activating events that promote enhanced expression of key proinflammatory molecules implicated in vascular injury. In this study, we investigated genetic polymorphisms of the SETD7, SUV39H1, and SUV39H2 methyltransferases as predictors of risk for micro- and macrovascular complications in type 1 diabetes.
RESEARCH DESIGN AND METHODS In the Finnish Diabetic Nephropathy Study (FinnDiane) cohort, 37 tagging single nucleotide polymorphisms (SNPs) were genotyped in 2,991 individuals with type 1 diabetes and diabetic retinopathy, diabetic nephropathy, and cardiovascular disease. Seven SNPs were genotyped in the replication cohorts from the Steno Diabetes Center and All Ireland/Warren 3/Genetics of Kidneys in Diabetes (GoKinD) U.K. study.
RESULTS In a meta-analysis, the minor T allele of the exonic SNP rs17353856 in the SUV39H2 was associated with diabetic retinopathy (genotypic odds ratio 0.75, P = 1.2 × 10−4). The same SNP showed a trend toward an association with diabetic nephropathy as well as cardiovascular disease in the FinnDiane cohort.
CONCLUSIONS Our findings propose that a genetic variation in a gene coding for a histone methyltransferase is protective for a diabetic microvascular complication. The pathophysiological implications of this polymorphism or other genetic variation nearby for the vascular complications of type 1 diabetes remain to be investigated.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db11-0073/-/DC1.
- Received January 21, 2011.
- Accepted July 11, 2011.
- © 2011 by the American Diabetes Association.
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