Abstract: Aims/hypothesis Recently, three groups independently reported that genetic variation in... more Abstract: Aims/hypothesis Recently, three groups independently reported that genetic variation in MTNR1B, the gene encoding melatonin receptor 1B, was associated with an increased risk of type 2 diabetes, increased fasting plasma glucose and impaired insulin secretion in populations of European ancestry. In the present study, we investigated whether a single MTNR1B polymorphism was associated with type 2 diabetes in Han Chinese individuals, to elucidate if this is a cross-populational effect. Methods The MTNR1B variant rs10830963 was genotyped in 1165 type 2 diabetic patients and 1105 normoglycaemic control individuals of Southern Han Chinese ancestry who were residents of the metropolitan area of Shanghai. The risk of developing type 2 diabetes was calculated using a logistic regression model adjusted for age, sex and BMI. A possible association with fasting plasma glucose was analysed in the normoglycaemic control individuals using a multiple linear regression analysis with adjust...
It is well established that exercise promotes health, and reduces people’s risks for developing t... more It is well established that exercise promotes health, and reduces people’s risks for developing type 2 diabetes and becoming obese. But just how exercise performs this, at a cellular level, and what molecular and physiologic steps are involved and in what order, are still not fully understood. Metabolic disorders are often influenced by interactions between genetic and environmental factors. One possible explanation for how the environment may influence the genome is through epigenetic mechanisms–that is–chemical modifications to the DNA itself. Epigenetic factors include, for example, DNA methylation, histone modifications, and different RNA-mediated processes, which all have the ability to bind to DNA or affect the chromatin structure and thereby change how specific genes are interpreted and expressed. In this short review, we focus on describing how exercise influences the genome-wide DNA methylation pattern, including candidate genes for obesity and type 2 diabetes, in human adi...
The identification of individuals with a high risk of developing type 2 diabetes (T2D) is fundamen... more The identification of individuals with a high risk of developing type 2 diabetes (T2D) is fundamental for prevention. Here, we used a translational approach and prediction criteria to identify changes in DNA methylation visible before the development of T2D. Islets of Langerhans were isolated from genetically identical 10-week-old female New Zealand Obese mice which differ in their degree of hyperglycemia and in liver fat content. The application of a semi-explorative approach identified 497 differentially expressed and methylated genes (p-value=6.42e-09, hypergeometric test) enriched in pathways linked to insulin secretion and ECM-receptor interaction. The comparison of mouse data with DNA methylation levels of incident T2D cases from the prospective EPIC-Potsdam cohort, revealed 105 genes with altered DNA methylation at 605 CpG sites which were associated with future T2D. AKAP13, TENM2, CTDSPL, PTPRN2 and PTPRS showed the strongest predictive potential (ROC-AUC values 0.62-0.73). Among the new candidates identified in blood cells, 655 CpG sites, located in 99 genes, were differentially methylated in islets of human with T2D. Utilizing correction for multiple testing detected 236 genes with an altered DNA methylation in blood cells and 201 genes in diabetic islets. Thus, the introduced translational approach identified novel putative biomarkers for early pancreatic islet aberrations preceding T2D.
An amendment to this paper has been published and can be accessed via a link at the top of the pa... more An amendment to this paper has been published and can be accessed via a link at the top of the paper.
To study the impact of aging on DNA methylation and mRNA expression in human liver. We analysed g... more To study the impact of aging on DNA methylation and mRNA expression in human liver. We analysed genome-wide DNA methylation and gene expression in human liver samples using Illumina 450K and HumanHT12 expression BeadChip arrays. DNA methylation analysis of ∼455,000 CpG sites in human liver revealed that age was significantly associated with altered DNA methylation of 20,396 CpG sites. Comparison of liver methylation data with published methylation data in other tissues showed that vast majority of the age-associated significant CpG sites overlapped between liver and blood, whereas a smaller overlap was found between liver and pancreatic islets or adipose tissue, respectively. We identified 151 genes whose liver expression also correlated with age. We identified age-associated DNA methylation and expression changes in human liver that are partly reflected by epigenetic alterations in blood.
Individuals who had a low birthweight (LBW) are at an increased risk of insulin resistance and ty... more Individuals who had a low birthweight (LBW) are at an increased risk of insulin resistance and type 2 diabetes when exposed to high-fat overfeeding (HFO). We studied genome-wide mRNA expression and DNA methylation in subcutaneous adipose tissue (SAT) after 5 days of HFO and after a control diet in 40 young men, of whom 16 had LBW. mRNA expression was analysed using Affymetrix Human Gene 1.0 ST arrays and DNA methylation using Illumina 450K BeadChip arrays. We found differential DNA methylation at 53 sites in SAT from LBW vs normal birthweight (NBW) men (false discovery rate <5%), including sites in the FADS2 and CPLX1 genes previously associated with type 2 diabetes. When we used reference-free cell mixture adjustments to potentially adjust for cell composition, 4,323 sites had differential methylation in LBW vs NBW men. However, no differences in SAT gene expression levels were identified between LBW and NBW men. In the combined group of all 40 participants, 3,276 genes (16.5%) ...
Type 2 diabetes (T2D) develops due to insulin resistance and impaired insulin secretion, predomin... more Type 2 diabetes (T2D) develops due to insulin resistance and impaired insulin secretion, predominantly in genetically predisposed subjects exposed to nongenetic risk factors like obesity, physical inactivity and ageing. Emerging data suggest that epigenetics also play a key role in the pathogenesis of T2D. Genome-wide studies have identified altered DNA methylation patterns in pancreatic islets, skeletal muscle and adipose tissue from subjects with T2D compared with nondiabetic controls. Environmental factors known to affect T2D, including obesity, exercise and diet, have also been found to alter the human epigenome. Additionally, ageing and the intrauterine environment are associated with differential DNA methylation. Together, these data highlight a key role for epigenetics and particularly DNA methylation in the growing incidence of T2D.
Abstract: Aims/hypothesis Recently, three groups independently reported that genetic variation in... more Abstract: Aims/hypothesis Recently, three groups independently reported that genetic variation in MTNR1B, the gene encoding melatonin receptor 1B, was associated with an increased risk of type 2 diabetes, increased fasting plasma glucose and impaired insulin secretion in populations of European ancestry. In the present study, we investigated whether a single MTNR1B polymorphism was associated with type 2 diabetes in Han Chinese individuals, to elucidate if this is a cross-populational effect. Methods The MTNR1B variant rs10830963 was genotyped in 1165 type 2 diabetic patients and 1105 normoglycaemic control individuals of Southern Han Chinese ancestry who were residents of the metropolitan area of Shanghai. The risk of developing type 2 diabetes was calculated using a logistic regression model adjusted for age, sex and BMI. A possible association with fasting plasma glucose was analysed in the normoglycaemic control individuals using a multiple linear regression analysis with adjust...
It is well established that exercise promotes health, and reduces people’s risks for developing t... more It is well established that exercise promotes health, and reduces people’s risks for developing type 2 diabetes and becoming obese. But just how exercise performs this, at a cellular level, and what molecular and physiologic steps are involved and in what order, are still not fully understood. Metabolic disorders are often influenced by interactions between genetic and environmental factors. One possible explanation for how the environment may influence the genome is through epigenetic mechanisms–that is–chemical modifications to the DNA itself. Epigenetic factors include, for example, DNA methylation, histone modifications, and different RNA-mediated processes, which all have the ability to bind to DNA or affect the chromatin structure and thereby change how specific genes are interpreted and expressed. In this short review, we focus on describing how exercise influences the genome-wide DNA methylation pattern, including candidate genes for obesity and type 2 diabetes, in human adi...
The identification of individuals with a high risk of developing type 2 diabetes (T2D) is fundamen... more The identification of individuals with a high risk of developing type 2 diabetes (T2D) is fundamental for prevention. Here, we used a translational approach and prediction criteria to identify changes in DNA methylation visible before the development of T2D. Islets of Langerhans were isolated from genetically identical 10-week-old female New Zealand Obese mice which differ in their degree of hyperglycemia and in liver fat content. The application of a semi-explorative approach identified 497 differentially expressed and methylated genes (p-value=6.42e-09, hypergeometric test) enriched in pathways linked to insulin secretion and ECM-receptor interaction. The comparison of mouse data with DNA methylation levels of incident T2D cases from the prospective EPIC-Potsdam cohort, revealed 105 genes with altered DNA methylation at 605 CpG sites which were associated with future T2D. AKAP13, TENM2, CTDSPL, PTPRN2 and PTPRS showed the strongest predictive potential (ROC-AUC values 0.62-0.73). Among the new candidates identified in blood cells, 655 CpG sites, located in 99 genes, were differentially methylated in islets of human with T2D. Utilizing correction for multiple testing detected 236 genes with an altered DNA methylation in blood cells and 201 genes in diabetic islets. Thus, the introduced translational approach identified novel putative biomarkers for early pancreatic islet aberrations preceding T2D.
An amendment to this paper has been published and can be accessed via a link at the top of the pa... more An amendment to this paper has been published and can be accessed via a link at the top of the paper.
To study the impact of aging on DNA methylation and mRNA expression in human liver. We analysed g... more To study the impact of aging on DNA methylation and mRNA expression in human liver. We analysed genome-wide DNA methylation and gene expression in human liver samples using Illumina 450K and HumanHT12 expression BeadChip arrays. DNA methylation analysis of ∼455,000 CpG sites in human liver revealed that age was significantly associated with altered DNA methylation of 20,396 CpG sites. Comparison of liver methylation data with published methylation data in other tissues showed that vast majority of the age-associated significant CpG sites overlapped between liver and blood, whereas a smaller overlap was found between liver and pancreatic islets or adipose tissue, respectively. We identified 151 genes whose liver expression also correlated with age. We identified age-associated DNA methylation and expression changes in human liver that are partly reflected by epigenetic alterations in blood.
Individuals who had a low birthweight (LBW) are at an increased risk of insulin resistance and ty... more Individuals who had a low birthweight (LBW) are at an increased risk of insulin resistance and type 2 diabetes when exposed to high-fat overfeeding (HFO). We studied genome-wide mRNA expression and DNA methylation in subcutaneous adipose tissue (SAT) after 5 days of HFO and after a control diet in 40 young men, of whom 16 had LBW. mRNA expression was analysed using Affymetrix Human Gene 1.0 ST arrays and DNA methylation using Illumina 450K BeadChip arrays. We found differential DNA methylation at 53 sites in SAT from LBW vs normal birthweight (NBW) men (false discovery rate <5%), including sites in the FADS2 and CPLX1 genes previously associated with type 2 diabetes. When we used reference-free cell mixture adjustments to potentially adjust for cell composition, 4,323 sites had differential methylation in LBW vs NBW men. However, no differences in SAT gene expression levels were identified between LBW and NBW men. In the combined group of all 40 participants, 3,276 genes (16.5%) ...
Type 2 diabetes (T2D) develops due to insulin resistance and impaired insulin secretion, predomin... more Type 2 diabetes (T2D) develops due to insulin resistance and impaired insulin secretion, predominantly in genetically predisposed subjects exposed to nongenetic risk factors like obesity, physical inactivity and ageing. Emerging data suggest that epigenetics also play a key role in the pathogenesis of T2D. Genome-wide studies have identified altered DNA methylation patterns in pancreatic islets, skeletal muscle and adipose tissue from subjects with T2D compared with nondiabetic controls. Environmental factors known to affect T2D, including obesity, exercise and diet, have also been found to alter the human epigenome. Additionally, ageing and the intrauterine environment are associated with differential DNA methylation. Together, these data highlight a key role for epigenetics and particularly DNA methylation in the growing incidence of T2D.
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Papers by Tina Rönn