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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

Genotyped SNPs in the chr10:14,959,424−14,996,308 location (NCBI36 assembly). All putative exons are marked with boxes, and UTR regions are marked with arrows.
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Figure 1: Genotyped SNPs in the chr10:14,959,424−14,996,308 location (NCBI36 assembly). All putative exons are marked with boxes, and UTR regions are marked with arrows.

Mentions: A total of 23 SNPs out of 25 tagSNPs within SETD7 were successfully genotyped in the discovery cohort. The rs7680948 was left out from the iPlex because of primer failures, and rs4863655 located 9.7 kb from the gene failed genotyping and was excluded from the analysis. The rs3373 in SUV39H1 was successfully genotyped, but one male patient was heterozygous for this X-chromosomal SNP and was excluded from the analysis. Nine tagSNPs out of 11 in SUV39H2 were successfully genotyped (Fig. 1). The rs17156024 failed in genotyping and rs7922341 gave unreliable genotyping results that were studied further with PCR and sequencing. The results still showed unreliable genotype calling (data not shown), and rs7922341 genotypes were excluded. Altogether, genotypes were successfully called for 33 SNPs with average success rates of 0.982, 0.982, and 0.984 for SETD7, SUV39H1, and SUV39H2, respectively (genotypes provided in Supplementary Tables 2–4). All samples with a genotyping success rate of ≥0.75 were included in further analyses.


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)

Genotyped SNPs in the chr10:14,959,424−14,996,308 location (NCBI36 assembly). All putative exons are marked with boxes, and UTR regions are marked with arrows.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 1: Genotyped SNPs in the chr10:14,959,424−14,996,308 location (NCBI36 assembly). All putative exons are marked with boxes, and UTR regions are marked with arrows.
Mentions: A total of 23 SNPs out of 25 tagSNPs within SETD7 were successfully genotyped in the discovery cohort. The rs7680948 was left out from the iPlex because of primer failures, and rs4863655 located 9.7 kb from the gene failed genotyping and was excluded from the analysis. The rs3373 in SUV39H1 was successfully genotyped, but one male patient was heterozygous for this X-chromosomal SNP and was excluded from the analysis. Nine tagSNPs out of 11 in SUV39H2 were successfully genotyped (Fig. 1). The rs17156024 failed in genotyping and rs7922341 gave unreliable genotyping results that were studied further with PCR and sequencing. The results still showed unreliable genotype calling (data not shown), and rs7922341 genotypes were excluded. Altogether, genotypes were successfully called for 33 SNPs with average success rates of 0.982, 0.982, and 0.984 for SETD7, SUV39H1, and SUV39H2, respectively (genotypes provided in Supplementary Tables 2–4). All samples with a genotyping success rate of ≥0.75 were included in further analyses.

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