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Genetic examination of SETD7 and SUV39H1/H2 methyltransferases and the risk of diabetes complications in patients with type 1 diabetes.

Syreeni A, El-Osta A, Forsblom C, Sandholm N, Parkkonen M, Tarnow L, Parving HH, McKnight AJ, Maxwell AP, Cooper ME, Groop PH, FinnDiane Study Gro - Diabetes (2011)

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland.

ABSTRACT

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.

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Related in: MedlinePlus

The rs17353856 C allele frequencies (white bars) and genotype CGG/CGG frequencies (black line) in the complication score groups. The CGG genotype consists of rs17353856 C allele (major), rs7900814 G allele (major), and rs12572872 G allele (major). The complication score groups are formed as follows: 0 = no vascular complications; 1 = diabetic nephropathy or retinopathy; 2 = diabetic nephropathy and retinopathy or CVD; 3 = CVD + diabetic nephropathy or retinopathy; and 4 = CVD, diabetic nephropathy, and retinopathy. P values are from the χ2 linear by linear association test.
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Figure 2: The rs17353856 C allele frequencies (white bars) and genotype CGG/CGG frequencies (black line) in the complication score groups. The CGG genotype consists of rs17353856 C allele (major), rs7900814 G allele (major), and rs12572872 G allele (major). The complication score groups are formed as follows: 0 = no vascular complications; 1 = diabetic nephropathy or retinopathy; 2 = diabetic nephropathy and retinopathy or CVD; 3 = CVD + diabetic nephropathy or retinopathy; and 4 = CVD, diabetic nephropathy, and retinopathy. P values are from the χ2 linear by linear association test.

Mentions: Interestingly, rs17353856 is the same exonic SNP associated with diabetic retinopathy as well as diabetic nephropathy in the FinnDiane cohort. Therefore, we calculated a complication score for each patient. Groups were assessed by the presence of diabetic vascular complications: 0 = no vascular complication; 1 = retinopathy or nephropathy; 2 = retinopathy + nephropathy or CVD; 3 = retinopathy and CVD or nephropathy and CVD; and 4 = retinopathy, nephropathy, and CVD. The rs17353856 major allele C frequencies increased with increasing complication score (P = 5.7 × 10−4) (Fig. 2 and Supplementary Table 9). However, a similar trend could not be replicated in the Steno cohort.


Genetic examination of SETD7 and SUV39H1/H2 methyltransferases and the risk of diabetes complications in patients with type 1 diabetes.

Syreeni A, El-Osta A, Forsblom C, Sandholm N, Parkkonen M, Tarnow L, Parving HH, McKnight AJ, Maxwell AP, Cooper ME, Groop PH, FinnDiane Study Gro - Diabetes (2011)

The rs17353856 C allele frequencies (white bars) and genotype CGG/CGG frequencies (black line) in the complication score groups. The CGG genotype consists of rs17353856 C allele (major), rs7900814 G allele (major), and rs12572872 G allele (major). The complication score groups are formed as follows: 0 = no vascular complications; 1 = diabetic nephropathy or retinopathy; 2 = diabetic nephropathy and retinopathy or CVD; 3 = CVD + diabetic nephropathy or retinopathy; and 4 = CVD, diabetic nephropathy, and retinopathy. P values are from the χ2 linear by linear association test.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3198095&req=5

Figure 2: The rs17353856 C allele frequencies (white bars) and genotype CGG/CGG frequencies (black line) in the complication score groups. The CGG genotype consists of rs17353856 C allele (major), rs7900814 G allele (major), and rs12572872 G allele (major). The complication score groups are formed as follows: 0 = no vascular complications; 1 = diabetic nephropathy or retinopathy; 2 = diabetic nephropathy and retinopathy or CVD; 3 = CVD + diabetic nephropathy or retinopathy; and 4 = CVD, diabetic nephropathy, and retinopathy. P values are from the χ2 linear by linear association test.
Mentions: Interestingly, rs17353856 is the same exonic SNP associated with diabetic retinopathy as well as diabetic nephropathy in the FinnDiane cohort. Therefore, we calculated a complication score for each patient. Groups were assessed by the presence of diabetic vascular complications: 0 = no vascular complication; 1 = retinopathy or nephropathy; 2 = retinopathy + nephropathy or CVD; 3 = retinopathy and CVD or nephropathy and CVD; and 4 = retinopathy, nephropathy, and CVD. The rs17353856 major allele C frequencies increased with increasing complication score (P = 5.7 × 10−4) (Fig. 2 and Supplementary Table 9). However, a similar trend could not be replicated in the Steno cohort.

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland.

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus