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1.  Impact of the Hypoxia-Inducible Factor-1 α (HIF1A) Pro582Ser Polymorphism on Diabetes Nephropathy 
Diabetes Care  2013;36(2):415-421.
OBJECTIVE
Hypoxia plays a major pathogenic role in diabetic nephropathy (DN). We have investigated in this study the effect of hypoxia-inducible factor 1 α subunit (HIF1A) genetic polymorphisms on the development of DN.
RESEARCH DESIGN AND METHODS
In 1,165 American type 1 diabetic patients with and without DN selected from the Genetics of Kidneys in Diabetes (GoKinD) study, the HIF1A genetic polymorphisms were genotyped with TaqMan allelic discrimination. The regulation of HIF-1α in the kidneys of diabetic mice was appreciated by immunohistochemistry, and the effect HIF1A Pro582Ser polymorphism on HIF-1α sensitivity to glucose was evaluated in vitro.
RESULTS
We identified a protective association between HIF1A Pro582Ser polymorphism and DN in male subjects. We also provided mechanistic insights that HIF-1α is repressed in the medulla of diabetic mice despite hypoxia and that Pro582Ser polymorphism confers less sensitivity to the inhibitory effect of glucose during a hypoxic challenge.
CONCLUSIONS
The current study demonstrates for the first time that HIF1A Pro582Ser polymorphism has an effect on DN, possibly by conferring a relative resistance to the repressive effect of glucose on HIF-1α.
doi:10.2337/dc12-1125
PMCID: PMC3554309  PMID: 22991450
2.  Evaluation of the Association of Plasma Pentraxin 3 Levels with Type 2 Diabetes and Diabetic Nephropathy in a Malay Population 
Journal of Diabetes Research  2013;2013:298019.
Recent reports have demonstrated that elevated plasma long pentraxin 3 (PTX3) levels are associated with cardiovascular and chronic kidney diseases. In the current study, we investigated the plasma PTX3 levels in 296 Malay subjects including the subjects with normal glucose tolerance (NGT) and type 2 diabetes (T2DM) patients with or without DN by using an enzyme-linked immune-sorbent assay. Results showed that in males, plasma PTX3 levels in T2DM patients without DN were lower than that in the subjects with NGT (2.78 versus 3.98 ng/mL; P = 0.021). Plasma PTX3 levels in T2DM patients with DN were decreased compared to the patients without DN (1.63 versus 2.78 ng/mL; P = 0.013). In females, however, no significant alteration of plasma PTX3 levels among NGT subjects and T2DM patients with and without DN was detected. Furthermore, an inverse correlation between PTX3 and body mass index was found in male subjects with NGT (P = 0.012; r = −0.390), but not in male T2DM patients, neither in all females. The current study provided the first evidence that decreased plasma PTX3 levels are associated with T2DM and DN in Malay men and also suggested that PTX3 may have different effects in DN and chronic kidney diseases.
doi:10.1155/2013/298019
PMCID: PMC3854091  PMID: 24350299
3.  Increased expression of adenylyl cyclase 3 in pancreatic islets and central nervous system of diabetic Goto-Kakizaki rats 
Islets  2012;4(5):343-348.
Adenylyl cyclase 3 (AC3) is expressed in pancreatic islets of the Goto-Kakizaki (GK) rat, a spontaneous animal model of type 2 diabetes (T2D), and also exerts genetic effects on the regulation of body weight in man. In addition to pancreatic islets, the central nervous system (CNS) plays an important role in the pathogenesis of T2D and obesity by regulating feeding behavior, body weight and glucose metabolism. In the present study, we have investigated AC3 expression in pancreatic islets, striatum and hypothalamus of GK rats to evaluate its role in the regulation of glucose homeostasis. GK and Wistar rats at the age of 2.5 mo were used. A group of GK rats were implanted with sustained insulin release chips for 15 d. Plasma glucose and serum insulin levels were measured. AC3 gene expression levels in pancreatic islets, striatum and hypothalamus were determined by using real-time RT-PCR. Results indicated that plasma glucose levels in Wistar rats were found to be similar to insulin-treated GK rats, and significantly lower compared with non-treated GK rats. AC3 expression levels in pancreatic islets, striatum and hypothalamus of GK rats were higher compared with Wistar rats, while the levels were intermediate in insulin-treated GK rats. The AC3 expression display patterns between pancreatic islets and striatum-hypothalamus were similar. The present study thus provides the first evidence that AC3 is overexpressed in the regions of striatum and hypothalamus of brain, and similarly in pancreatic islets of GK rats suggesting that AC3 plays a role in regulation of glucose homeostasis via CNS and insulin secretion.
doi:10.4161/isl.22283
PMCID: PMC3524141  PMID: 23018249
Adenylyl cyclase 3; body weight; central nervous system; glucose; pancreatic islets; type 2 diabetes
4.  Epigenetic analyses of the insulin-like growth factor binding protein 1 gene in type 1 diabetes and diabetic nephropathy 
Clinical Epigenetics  2014;6(1):10.
Background
Clinical observations have demonstrated that high levels of circulating insulin-like growth factor binding protein-1 (IGFBP-1) are associated with type 1 diabetes (T1D), whereas low serum IGFBP-1 levels are associated with the risk of type 2 diabetes (T2D). Recently, we reported that increased DNA methylation levels in the IGFBP1 gene were associated with T2D. In the present study, we evaluated the epigenetic changes of IGFBP1 in T1D and diabetic nephropathy (DN).
Results
In total, 778 Swedish individuals, including T1D patients with or without DN and subjects with the normal glucose tolerance (NGT), were involved in the study. IGFBP1 methylation levels in genomic DNA extracted from peripheral blood were analyzed with bisulfite pyrosequencing. Serum IGFBP-1 levels were measured with radioimmunoassay. We found that DNA methylation levels in the IGFBP1 gene were decreased (15.6% versus 16.9%; P < 0.001), whereas serum IGFBP-1 levels were increased (31 versus 24 μg/L, P = 0.003) in T1D patients compared with NGT subjects. Furthermore, T1D patients with DN had increased circulating IGFBP-1 concentration compared with the patients without DN (52 versus 28 μg/L; P = 0.006). However, no difference of the IGFBP1 DNA methylation levels between T1D patients with and without DN was observed.
Conclusions
This study shows for the first time that T1D patients had decreased DNA methylation levels in the IGFBP1 gene and further implies that increased circulating IGFBP-1 levels are associated with T1D and DN.
doi:10.1186/1868-7083-6-10
PMCID: PMC4046502  PMID: 24904693
IGFBP1; DNA methylation; Type 1 diabetes; Diabetic nephropathy
5.  Association of intercellular adhesion molecule 1 (ICAM1) with diabetes and diabetic nephropathy 
Diabetes and diabetic nephropathy are complex diseases affected by genetic and environmental factors. Identification of the susceptibility genes and investigation of their roles may provide useful information for better understanding of the pathogenesis and for developing novel therapeutic approaches. Intercellular adhesion molecule 1 (ICAM1) is a cell surface glycoprotein expressed on endothelial cells and leukocytes in the immune system. The ICAM1 gene is located on chromosome 19p13 within the linkage region of diabetes. In the recent years, accumulating reports have implicated that genetic polymorphisms in the ICAM1 gene are associated with diabetes and diabetic nephropathy. Serum ICAM1 levels in diabetes patients and the icam1 gene expression in kidney tissues of diabetic animals are increased compared to the controls. Therefore, ICAM1 may play a role in the development of diabetes and diabetic nephropathy. In this review, we present genomic structure, variation, and regulation of the ICAM1 gene, summarized genetic and biological studies of this gene in diabetes and diabetic nephropathy and discussed about the potential application using ICAM1 as a biomarker and target for prediction and treatment of diabetes and diabetic nephropathy.
doi:10.3389/fendo.2012.00179
PMCID: PMC3551242  PMID: 23346076
intercellular adhesion molecule 1; diabetic nephropathy; end-stage renal disease; type 1 diabetes mellitus; type 2 diabetes mellitus
6.  Evaluation of the Association Between the ADRA2A Genetic Polymorphisms and Type 2 Diabetes in a Chinese Han Population 
Alpha-2-adrenergic receptor (ADRA2A) is involved in the sympathetic nervous system and plays a role in the regulation of insulin secretion and lipolysis. Recent studies have indicated that the ADRA2A polymorphisms are associated with type 2 diabetes (T2DM) in Caucasians and African Americans. The present study aimed to evaluate the association between the ADRA2A polymorphisms and T2DM in a Chinese Han population. Two single-nucleotide polymorphisms (SNPs) rs521674 and rs553668 in the ADRA2A gene were genotyped in 2094 Chinese subjects (1042 T2DM patients and 1052 nondiabetic controls) by using the TaqMan allelic discrimination technique. A single-locus analysis indicated that SNP rs553668 was associated with T2DM (p=0.04). Further analysis indicated that the association of SNP rs553668 was found in T2DM patients with body mass index (BMI)<25 kg/m2 (p=0.03), but not in the patients with BMI≥25 kg/m2 (p=0.56). This association was still significant in a recessive model (p=0.01, odds ratio=0.68, 95% confidence interval=0.51–0.92). In conclusion, the present study provides evidence that the ADRA2A polymorphism, rs553668, is associated with lean T2DM patients in a Chinese Han population. Further investigation to explore the role of ADRA2A in the regulation of body weight has been taken into our consideration.
doi:10.1089/gtmb.2012.0189
PMCID: PMC3501114  PMID: 23153004
7.  Increased DNA methylation levels of the insulin-like growth factor binding protein 1 gene are associated with type 2 diabetes in Swedish men 
Clinical Epigenetics  2013;5(1):21.
Background
Prospective studies have shown that low levels of circulating insulin-like growth factor binding protein-1 (IGFBP-1) are associated with the risk of type 2 diabetes. In the present study, we investigated DNA methylation in the IGFBP1 gene to evaluate its changes in relation to serum IGFBP-1 levels in type 2 diabetes.
Results
A total of 406 Swedish men, including age-matched normal glucose tolerance subjects and type 2 diabetes patients either newly diagnosed or undergoing treatment, were selected from the Stockholm Diabetes Prevention Program. IGFBP1 methylation levels in genomic DNA extracted from peripheral blood were analysed by bisulfite pyrosequencing. Serum IGFBP-1 levels were measured by radio-immunoassay. We found that IGFBP1 DNA methylation levels were higher in both newly diagnosed and treated type 2 diabetes patients with a mean diabetes duration of 3 years compared with subjects with normal glucose tolerance (19.8% and 20.2% vs. 16.9%, P < 0.001 for both). Serum levels of IGFBP-1 in newly diagnosed and in treated type 2 diabetes patients were lower compared with healthy individuals (18 μg/l both vs. 24 μg/l, P = 0.011, P < 0.001). IGFBP1 methylation levels but not serum IGFBP-1 levels in type 2 diabetes patients were independent of body mass index. Newly diagnosed patients with a family history of diabetes (FHD) had higher IGFBP1 methylation levels than those without FHD (20.3% vs. 18.6%, P = 0.017).
Conclusions
This study provides the first evidence that changes in DNA methylation of the IGFBP1 gene are associated with type 2 diabetes in Swedish men and suggests that increased IGFBP1 DNA methylation and decreased IGFBP-1 serum levels are features of type 2 diabetes with a short duration.
doi:10.1186/1868-7083-5-21
PMCID: PMC3843565  PMID: 24246027
IGFBP-1; DNA methylation; type 2 diabetes
8.  Antidiabetic Effect of Oral Borapetol B Compound, Isolated from the Plant Tinospora crispa, by Stimulating Insulin Release 
Aims. To evaluate the antidiabetic properties of borapetol B known as compound 1 (C1) isolated from Tinospora crispa in normoglycemic control Wistar (W) and spontaneously type 2 diabetic Goto-Kakizaki (GK) rats. Methods. The effect of C1 on blood glucose and plasma insulin was assessed by an oral glucose tolerance test. The effect of C1 on insulin secretion was assessed by batch incubation and perifusion experiments using isolated pancreatic islets. Results. An acute oral administration of C1 improved blood glucose levels in treated versus placebo groups with areas under glucose curves 0–120 min being 72 ± 17 versus 344 ± 10 mmol/L (P < 0.001) and 492 ± 63 versus 862 ± 55 mmol/L (P < 0.01) in W and GK rats, respectively. Plasma insulin levels were increased by 2-fold in treated W and GK rats versus placebo group at 30 min (P < 0.05). C1 dose-dependently increased insulin secretion from W and GK isolated islets at 3.3 mM and 16.7 mM glucose. The perifusions of isolated islets indicated that C1 did not cause leakage of insulin by damaging islet beta cells (P < 0.001). Conclusion. This study provides evidence that borapetol B (C1) has antidiabetic properties mainly due to its stimulation of insulin release.
doi:10.1155/2013/727602
PMCID: PMC3844206  PMID: 24319481
9.  Evaluation of IGFBP-7 DNA methylation changes and serum protein variation in Swedish subjects with and without type 2 diabetes 
Clinical Epigenetics  2013;5(1):20.
Background
Insulin-like growth factor-binding protein 7 (IGFBP-7) is able to interact with insulin-like growth factor 1 (IGF-1) as well as insulin. Previous studies have suggested that serum IGFBP-7 levels may be associated with insulin resistance in type 2 diabetes (T2D). This study aimed to evaluate IGFBP-7 serum protein and IGFBP7 DNA methylation levels in the subjects with and without T2D.
Results
A total of 340 Swedish subjects including 100 newly diagnosed T2D patients (50 women/50 men), 100 age-matched nondiabetic control subjects (50/50) and 140 treated T2D patients (54/86) were studied. Serum IGFBP-7 levels were measured with a novel ELISA. IGF1, IGFBP-1, and insulin were determined by in-house radioimmunoassays. DNA methylation levels in the IGFBP7 gene were analyzed with a bisulfite-pyrosequencing technique. Serum IGFBP-7 protein levels were similar among nondiabetic subjects, newly diagnosed, and treated T2D patients and were not correlated with IGFBP7 DNA methylation. However, IGFBP7 DNA methylation was increased in men with newly diagnosed T2D compared with nondiabetic controls (17.6% vs. 12.5%, P < 0.01). Serum IGFBP-7 levels correlated (r = 0.331, P = 0.019) with serum IGFBP-1 levels, a marker of insulin production, in men but not women with newly diagnosed T2D.
Conclusions
This study demonstrates for the first time that IGFBP7 DNA methylation levels are increased in Swedish men with newly diagnosed T2D. The correlation between IGFBP-7 and IGFBP-1 suggests that low IGFBP-7 may be associated with insulin resistance in T2D.
doi:10.1186/1868-7083-5-20
PMCID: PMC3817812  PMID: 24180466
IGF-1; IGFBP-1; IGFBP-7; Insulin; Type 2 diabetes
10.  Labisia pumila Upregulates Peroxisome Proliferator-Activated Receptor Gamma Expression in Rat Adipose Tissues and 3T3-L1 Adipocytes 
Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-activated transcription factor that regulates lipid and glucose metabolism. We investigated the effects of Labisia pumila (LP) standardized water extract on PPARgamma transcriptional activity in adipocytes in vitro and in vivo. We used a rat model of dihydrotestosterone- (DHT-) induced polycystic ovary syndrome (PCOS), a condition characterized by insulin resistance. At 9 weeks of age, the PCOS rats were randomly subdivided into two groups: PCOS-LP (50 mg/kg/day of LP) and PCOS-control (1 mL of deionised water) for 4-5 weeks on the same schedule. Real-time RT-PCR was performed to determine the PPARgamma mRNA levels. LP upregulated PPARgamma mRNA level by 40% in the PCOS rats. Western blot analysis further demonstrated the increased PPARgamma protein levels in parallel with upregulation in mRNA. These observations were further proven by adipocytes culture. Differentiated 3T3-L1 adipocytes were treated with final concentration of 100 μg/mL LP and compared to untreated control and 10 μM of rosiglitazone (in type of thiazolidinediones). LP increased PPARgamma expressions at both mRNA and protein levels and enhanced the effect of glucose uptake in the insulin-resistant cells. The data suggest that LP may ameliorate insulin resistance in adipocytes via the upregulation of PPARgamma pathway.
doi:10.1155/2013/808914
PMCID: PMC3723002  PMID: 23935612
11.  Evaluation of Genetic Association and Expression Reduction of TRPC1 in the Development of Diabetic Nephropathy 
American journal of nephrology  2008;29(3):244-251.
Background/Aims
The TRPC1 gene on chromosome 3q22–24 resides within the linkage region for diabetic nephropa-thy (DN) in type 1 (T1D) and type 2 diabetes mellitus (T2D). A recent study has demonstrated that TRPC1 expression is reduced in the kidney of diabetic ZDF- and STZ-treated rats. The present study aimed to evaluate the genetic and functional role of TRPC1 in the development of DN.
Methods
Genetic association study was performed with two independent cohorts, including 1,177 T1D European Americans with or without DN from GoKinD population and 850 African-American subjects with T2D-associated end-stage renal disease (ESRD), or with hypertensive (non-diabetic) ESRD, and nondiabetic controls. Seven tag SNP markers derived from HapMap data (phase II) were genotyped. TRPC1 gene expression was examined using real time RT-PCR.
Results
No significant association of TRPC1 DNA polymorphisms with DN or ERSD was found in GoKinD and African-American populations. TRPC1 gene mRNA expression in kidney was found to be trendily reduced in 12-week and significantly in 26-week-old db/db mice.
Conclusions
TRPC1 genetic polymorphism may not fundamentally contribute to the development of DN, while reduction of the gene expression in kidney may be a late phenomenon of DN as seen in diabetic animal models.
doi:10.1159/000157627
PMCID: PMC2698220  PMID: 18802326
TRPC1 gene; Single-nucleotide polymorphism; Diabetic nephropathy; End-stage renal disease; Diabetes types 1 and 2
12.  Evaluation of Genetic Association and Expression Reduction of TRPC1 in the Development of Diabetic Nephropathy 
American Journal of Nephrology  2008;29(3):244-251.
Background/Aims
The TRPC1 gene on chromosome 3q22–24 resides within the linkage region for diabetic nephropathy (DN) in type 1 (T1D) and type 2 diabetes mellitus (T2D). A recent study has demonstrated that TRPC1 expression is reduced in the kidney of diabetic ZDF- and STZ-treated rats. The present study aimed to evaluate the genetic and functional role of TRPC1 in the development of DN.
Methods
Genetic association study was performed with two independent cohorts, including 1,177 T1D European Americans with or without DN from GoKinD population and 850 African-American subjects with T2D-associated end-stage renal disease (ESRD), or with hypertensive (non-diabetic) ESRD, and nondiabetic controls. Seven tag SNP markers derived from HapMap data (phase II) were genotyped. TRPC1 gene expression was examined using real time RT-PCR.
Results
No significant association of TRPC1 DNA polymorphisms with DN or ERSD was found in GoKinD and African-American populations. TRPC1 gene mRNA expression in kidney was found to be trendily reduced in 12-week and significantly in 26-week-old db/db mice.
Conclusions
TRPC1 genetic polymorphism may not fundamentally contribute to the development of DN, while reduction of the gene expression in kidney may be a late phenomenon of DN as seen in diabetic animal models.
doi:10.1159/000157627
PMCID: PMC2698220  PMID: 18802326
TRPC1 gene; Single-nucleotide polymorphism; Diabetic nephropathy; End-stage renal disease; Diabetes types 1 and 2
13.  Genome-Wide Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology of Type 2 Diabetes 
Strawbridge, Rona J. | Dupuis, Josée | Prokopenko, Inga | Barker, Adam | Ahlqvist, Emma | Rybin, Denis | Petrie, John R. | Travers, Mary E. | Bouatia-Naji, Nabila | Dimas, Antigone S. | Nica, Alexandra | Wheeler, Eleanor | Chen, Han | Voight, Benjamin F. | Taneera, Jalal | Kanoni, Stavroula | Peden, John F. | Turrini, Fabiola | Gustafsson, Stefan | Zabena, Carina | Almgren, Peter | Barker, David J.P. | Barnes, Daniel | Dennison, Elaine M. | Eriksson, Johan G. | Eriksson, Per | Eury, Elodie | Folkersen, Lasse | Fox, Caroline S. | Frayling, Timothy M. | Goel, Anuj | Gu, Harvest F. | Horikoshi, Momoko | Isomaa, Bo | Jackson, Anne U. | Jameson, Karen A. | Kajantie, Eero | Kerr-Conte, Julie | Kuulasmaa, Teemu | Kuusisto, Johanna | Loos, Ruth J.F. | Luan, Jian'an | Makrilakis, Konstantinos | Manning, Alisa K. | Martínez-Larrad, María Teresa | Narisu, Narisu | Nastase Mannila, Maria | Öhrvik, John | Osmond, Clive | Pascoe, Laura | Payne, Felicity | Sayer, Avan A. | Sennblad, Bengt | Silveira, Angela | Stančáková, Alena | Stirrups, Kathy | Swift, Amy J. | Syvänen, Ann-Christine | Tuomi, Tiinamaija | van 't Hooft, Ferdinand M. | Walker, Mark | Weedon, Michael N. | Xie, Weijia | Zethelius, Björn | Ongen, Halit | Mälarstig, Anders | Hopewell, Jemma C. | Saleheen, Danish | Chambers, John | Parish, Sarah | Danesh, John | Kooner, Jaspal | Östenson, Claes-Göran | Lind, Lars | Cooper, Cyrus C. | Serrano-Ríos, Manuel | Ferrannini, Ele | Forsen, Tom J. | Clarke, Robert | Franzosi, Maria Grazia | Seedorf, Udo | Watkins, Hugh | Froguel, Philippe | Johnson, Paul | Deloukas, Panos | Collins, Francis S. | Laakso, Markku | Dermitzakis, Emmanouil T. | Boehnke, Michael | McCarthy, Mark I. | Wareham, Nicholas J. | Groop, Leif | Pattou, François | Gloyn, Anna L. | Dedoussis, George V. | Lyssenko, Valeriya | Meigs, James B. | Barroso, Inês | Watanabe, Richard M. | Ingelsson, Erik | Langenberg, Claudia | Hamsten, Anders | Florez, Jose C.
Diabetes  2011;60(10):2624-2634.
OBJECTIVE
Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology.
RESEARCH DESIGN AND METHODS
We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates.
RESULTS
Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10−8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10−4), improved β-cell function (P = 1.1 × 10−5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10−6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets.
CONCLUSIONS
We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.
doi:10.2337/db11-0415
PMCID: PMC3178302  PMID: 21873549
14.  New Susceptibility Loci Associated with Kidney Disease in Type 1 Diabetes 
Sandholm, Niina | Salem, Rany M. | McKnight, Amy Jayne | Brennan, Eoin P. | Forsblom, Carol | Isakova, Tamara | McKay, Gareth J. | Williams, Winfred W. | Sadlier, Denise M. | Mäkinen, Ville-Petteri | Swan, Elizabeth J. | Palmer, Cameron | Boright, Andrew P. | Ahlqvist, Emma | Deshmukh, Harshal A. | Keller, Benjamin J. | Huang, Huateng | Ahola, Aila J. | Fagerholm, Emma | Gordin, Daniel | Harjutsalo, Valma | He, Bing | Heikkilä, Outi | Hietala, Kustaa | Kytö, Janne | Lahermo, Päivi | Lehto, Markku | Lithovius, Raija | Österholm, Anne-May | Parkkonen, Maija | Pitkäniemi, Janne | Rosengård-Bärlund, Milla | Saraheimo, Markku | Sarti, Cinzia | Söderlund, Jenny | Soro-Paavonen, Aino | Syreeni, Anna | Thorn, Lena M. | Tikkanen, Heikki | Tolonen, Nina | Tryggvason, Karl | Tuomilehto, Jaakko | Wadén, Johan | Gill, Geoffrey V. | Prior, Sarah | Guiducci, Candace | Mirel, Daniel B. | Taylor, Andrew | Hosseini, S. Mohsen | Parving, Hans-Henrik | Rossing, Peter | Tarnow, Lise | Ladenvall, Claes | Alhenc-Gelas, François | Lefebvre, Pierre | Rigalleau, Vincent | Roussel, Ronan | Tregouet, David-Alexandre | Maestroni, Anna | Maestroni, Silvia | Falhammar, Henrik | Gu, Tianwei | Möllsten, Anna | Cimponeriu, Danut | Ioana, Mihai | Mota, Maria | Mota, Eugen | Serafinceanu, Cristian | Stavarachi, Monica | Hanson, Robert L. | Nelson, Robert G. | Kretzler, Matthias | Colhoun, Helen M. | Panduru, Nicolae Mircea | Gu, Harvest F. | Brismar, Kerstin | Zerbini, Gianpaolo | Hadjadj, Samy | Marre, Michel | Groop, Leif | Lajer, Maria | Bull, Shelley B. | Waggott, Daryl | Paterson, Andrew D. | Savage, David A. | Bain, Stephen C. | Martin, Finian | Hirschhorn, Joel N. | Godson, Catherine | Florez, Jose C. | Groop, Per-Henrik | Maxwell, Alexander P.
PLoS Genetics  2012;8(9):e1002921.
Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS) of T1D DN comprising ∼2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2×10−8) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0×10−9). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-β1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1×10−7), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.
Author Summary
The global prevalence of diabetes has reached epidemic proportions, constituting a major health care problem worldwide. Diabetic kidney disease, or diabetic nephropathy (DN)—the major long term microvascular complication of diabetes—is associated with excess mortality among patients with type 1 diabetes. Even though DN has been shown to cluster in families, the underlying genetic and molecular pathways remain poorly defined. We have undertaken the largest genome-wide association study and meta-analysis to date on DN and on its most severe form of kidney disease, end-stage renal disease (ESRD). We identified new loci significantly associated with diabetic ESRD: AFF3 and an intergenic locus on chromosome 15q26 residing between RGMA and MCTP2. Our functional analyses suggest that AFF3 influences renal tubule fibrosis, a pathological hallmark of severe DN. Another locus in ERBB4 was suggestively associated with DN and resides in the same intronic region as a variant affecting the expression of ERBB4. Subsequent pathway analysis of the genes co-expressed with ERBB4 indicated involvement of fibrosis.
doi:10.1371/journal.pgen.1002921
PMCID: PMC3447939  PMID: 23028342
15.  Association between Regulator of G Protein Signaling 9–2 and Body Weight 
PLoS ONE  2011;6(11):e27984.
Regulator of G protein signaling 9–2 (RGS9–2) is a protein that is highly enriched in the striatum, a brain region that mediates motivation, movement and reward responses. We identified a naturally occurring 5 nucleotide deletion polymorphism in the human RGS9 gene and found that the mean body mass index (BMI) of individuals with the deletion was significantly higher than those without. A splicing reporter minigene assay demonstrated that the deletion had the potential to significantly decrease the levels of correctly spliced RGS9 gene product. We measured the weights of rats after virally transduced overexpression of RGS9–2 or the structurally related RGS proteins, RGS7, or RGS11, in the nucleus accumbens (NAc) and observed a reduction in body weight after overexpression of RGS9–2 but not RGS7 or 11. Conversely, we found that the RGS9 knockout mice were heavier than their wild-type littermates and had significantly higher percentages of abdominal fat. The constituent adipocytes were found to have a mean cross-sectional area that was more than double that of corresponding cells from wild-type mice. However, food intake and locomotion were not significantly different between the two strains. These studies with humans, rats and mice implicate RGS9–2 as a factor in regulating body weight.
doi:10.1371/journal.pone.0027984
PMCID: PMC3223194  PMID: 22132185
16.  Evaluation of the Association between the AC3 Genetic Polymorphisms and Obesity in a Chinese Han Population 
PLoS ONE  2010;5(11):e13851.
Background
AC3 is one of adenylyl cyclase isoforms involved in cAMP and insulin signaling pathway. Recent reports have demonstrated that the AC3 genetic polymorphisms are associated with obesity in a Swedish population. AC3 knock out mice exhibit obese when they age. These findings suggest that AC3 plays an important role in the regulation of body weight.
Methodology/Principal Findings
In the present study, we evaluated the association between the AC3 genetic polymorphisms and obesity in a Han Chinese population. A total of 2580 adults, including 1490 lean (BMI = 18.5–23.9), 677 overweight (BMI 24.0–27.9) and 413 obese (BMI ≥28.0) subjects were genotyped for 5 TagSNPs in the AC3 gene. Single maker association analyses indicated that SNP rs753529 was significantly associated with BMI in obese subjects (P = 0.022, OR = 0.775 95%CI = 0.623–0.963), but not in overweight subjects (P = 0.818). Multiple maker association analyses showed that the haplotype (G-G-G) constructed with SNPs rs1127568, rs7604576 and rs753529 was significantly associated with obesity (P = 0.029). Further genotyping of SNP rs753529 in 816 children, including 361 overweight subjects (BMI>P80) and 455 controls (BMI = P20–50) were performed, and no significant association with BMI was found. All tests were adjusted for age, sex, physical activity index, household income and/or diet expenses.
Conclusions
The present study provides replication evidence that the AC3 genetic polymorphisms are associated with decreased risk of obesity among adults but not in children in a Chinese Han population. The data also suggest that the AC3 genetic effects on BMI may have interaction with the factors related to ageing and environment.
doi:10.1371/journal.pone.0013851
PMCID: PMC2973974  PMID: 21079816
17.  Effects of MCF2L2, ADIPOQ and SOX2 genetic polymorphisms on the development of nephropathy in type 1 Diabetes Mellitus 
BMC Medical Genetics  2010;11:116.
Background
MCF2L2, ADIPOQ and SOX2 genes are located in chromosome 3q26-27, which is linked to diabetic nephropathy (DN). ADIPOQ and SOX2 genetic polymorphisms are found to be associated with DN. In the present study, we first investigated the association between MCF2L2 and DN, and then evaluated effects of these three genes on the development of DN.
Methods
A total of 1177 type 1 diabetes patients with and without DN from the GoKinD study were genotyped with TaqMan allelic discrimination. All subjects were of European descent.
Results
Leu359Ile T/G variant in the MCF2L2 gene was found to be associated with DN in female subjects (P = 0.017, OR = 0.701, 95%CI 0.524-0.938) but not in males. The GG genotype carriers among female patients with DN had tendency decreased creatinine and cystatin levels compared to the carriers with either TT or TG genotypes. This polymorphism MCF2L2-rs7639705 together with SNPs of ADIPOQ-rs266729 and SOX2-rs11915160 had combined effects on decreased risk of DN in females (P = 0.001).
Conclusion
The present study provides evidence that MCF2L2, ADIPOQ and SOX2 genetic polymorphisms have effects on the resistance of DN in female T1D patients, and suggests that the linkage with DN in chromosome 3q may be explained by the cumulated genetic effects.
doi:10.1186/1471-2350-11-116
PMCID: PMC2919463  PMID: 20667095
18.  The Common FTO Genetic Polymorphism rs9939609 is Associated with Increased BMI in Type 1 Diabetes but not with Diabetic Nephropathy 
Biomarker Insights  2010;5:29-32.
The fat mass and obesity associated (FTO) gene has an important genetic effect on body mass index (BMI) and risk of obesity, and obesity contributes to the progression of renal diseases, including diabetic nephropathy. We thus conducted a genetic association study to evaluate whether the FTO gene confers the risk susceptibility to the development of diabetic nephropathy. Genotyping experiments of the common FTO polymorphism, rs9939609, in 1170 type 1 diabetes patients with (n = 597) or without diabetic nephropathy (n = 573) were performed with TaqMan allelic discrimination. All subjects are of European descent and selected from the Genetics of Kidney Diseases in Diabetes (GoKinD) study. The frequency of T allele of this polymorphism was 0.414 in the studied population. There was no allelic association of this polymorphism with diabetic nephropathy. But, the risk susceptibility of A allele conferring to the increased BMI among type 1 diabetes patients was observed. The subjects carrying with AA genotype had higher BMI compared to the carriers with TA and/or TT genotype(s) (P ≤ 0.019). The present study provides evidence that the common FTO genetic polymorphism, rs9939609, is associated with increased BMI in type 1 diabetes but not with diabetic nephropathy.
PMCID: PMC2867633  PMID: 20467478
diabetic nephropathy; fat mass and obesity associated; genetic association; single nucleotide polymorphism
19.  Biomarkers of Adiponectin: Plasma Protein Variation and Genomic DNA Polymorphisms 
Biomarker Insights  2009;4:123-133.
Adiponectin is secreted by white adipose tissue and exists as the most abundant adipokine in the human plasma. Recent research has indicated that plasma adiponectin levels are inversely correlated with body mass index (BMI) and insulin resistance. Reduction of plasma adiponectin levels is commonly observed in the patients with type 2 diabetes (T2D) and/or in those who are obese in comparison with healthy control individuals. The adiponectin (AdipoQ) gene has a moderate linkage disequilibrium (LD), but two small LD blocks are observed, respectively, in the promoter region and the boundary of exon 2-intron 2. Genetic association studies have demonstrated that single nucleotide polymorphisms (SNPs) +45G15G(T/G) in exon 2 and +276G/T in intron 2 of the AdipoQ gene confer the risk susceptibility to the development of T2D, obesity and diabetic nephropathy (DN). The SNPs in the promoter region, including −11426A/G, −11377C/G and −11391G/A, are found to be associated with T2D and DN. Recent research has indicated that the promoter polymorphisms interfere with the AdipoQ promoter activity. The haplotypes constructed by the promoter polymorphisms and SNP +276G/T in intron 2 are associated with circulating adiponectin levels. This review summarises genetic and pathophysiological relevancies of adiponectin and discusses about the biomarkers of adiponectin plasma protein variation and genomic DNA polymorphisms.
PMCID: PMC2796863  PMID: 20029651
adiponectin; biomarker; genetic polymorphism; protein variation
20.  Evidence that the Gene Encoding Insulin Degrading Enzyme Influences Human Lifespan 
Human molecular genetics  2008;17(15):2370-2378.
Studies in model organisms have demonstrated that components of insulin and insulin-like signaling pathways are involved in the regulation of lifespan but the relevance of those findings to humans has remained obscure. Here we provide evidence suggesting that variants of the gene encoding insulin-degrading enzyme (IDE) may be influencing human lifespan. We have employed a variety of models and diverse samples that reproducibly indicate the relative change in IDE genotype frequency across the age spectrum as well as allow the detection of association with ageat-death. A tenable molecular basis of this is suggested by the observation of genetic association with both fasting plasma insulin levels and IDE mRNA expression. Across populations the emergent genetic model is indicative of over-dominance, where heterozygotes of critical markers have increased IDE mRNA expression and insulin levels, and this is reflected in diminished heterozygosity at advanced age. A critical and replicating feature of this study is that change in IDE genotype frequency with advancing age appears to only be occurring in men, and this is supported in that insulin levels are only associated with IDE in men. Results suggest a relationship between a gene that is intimately involved in insulin metabolism and the determination of lifespan in humans, but over-dominance and gender specificity will be important parameters to consider towards clarifying the biological importance of these findings.
doi:10.1093/hmg/ddn137
PMCID: PMC2574758  PMID: 18448515
21.  Evidence that the gene encoding insulin degrading enzyme influences human lifespan 
Human Molecular Genetics  2008;17(15):2370-2378.
Studies in model organisms have demonstrated that components of insulin and insulin-like signaling pathways are involved in the regulation of lifespan but the relevance of those findings to humans has remained obscure. Here we provide evidence suggesting that variants of the gene encoding insulin-degrading enzyme (IDE) may be influencing human lifespan. We have employed a variety of models and diverse samples that reproducibly indicate the relative change in IDE genotype frequency across the age spectrum as well as allow the detection of association with age-at-death. A tenable molecular basis of this is suggested by the observation of genetic association with both fasting plasma insulin levels and IDE mRNA expression. Across populations the emergent genetic model is indicative of over-dominance, where heterozygotes of critical markers have increased IDE mRNA expression and insulin levels, and this is reflected in diminished heterozygosity at advanced age. A critical and replicating feature of this study is that change in IDE genotype frequency with advancing age appears to be occurring only in men, and this is supported in that insulin levels are only associated with IDE in men. Results suggest a relationship between a gene that is intimately involved in insulin metabolism and the determination of lifespan in humans, but over-dominance and gender specificity will be important parameters to consider clarifying the biological importance of these findings.
doi:10.1093/hmg/ddn137
PMCID: PMC2574758  PMID: 18448515
22.  Functional and genetic analysis in type 2 diabetes of Liver X receptor alleles – a cohort study 
BMC Medical Genetics  2009;10:27.
Background
Liver X receptor alpha (LXRA) and beta (LXRB) regulate glucose and lipid homeostasis in model systems but their importance in human physiology is poorly understood. This project aimed to determine whether common genetic variations in LXRA and LXRB associate with type 2 diabetes (T2D) and quantitative measures of glucose homeostasis, and, if so, reveal the underlying mechanisms.
Methods
Eight common single nucleotide polymorphisms in LXRA and LXRB were analyzed for association with T2D in one French cohort (N = 988 cases and 941 controls), and for association with quantitative measures reflecting glucose homeostasis in two non-diabetic population-based samples comprising N = 697 and N = 1344 adults. Investigated quantitative phenotypes included fasting plasma glucose, serum insulin, and HOMAIR as measure of overall insulin resistance. An oral glucose tolerance test was performed in N = 1344 of adults. The two alleles of the proximal LXRB promoter, differing only at the SNP rs17373080, were cloned into reporter vectors and transiently transfected, whereupon allele-specific luciferase activity was measured. rs17373080 overlapped, according to in silico analysis, with a binding site for Nuclear factor 1 (NF1). Promoter alleles were tested for interaction with NF1 using direct DNA binding and transactivation assays.
Results
Genotypes at two LXRB promoter SNPs, rs35463555 and rs17373080, associated nominally with T2D (P values 0.047 and 0.026). No LXRA or LXRB SNP associated with quantitative measures reflecting glucose homeostasis. The rs17373080 C allele displayed higher basal transcription activity (P value < 0.05). The DNA-mobility shift assay indicated that oligonucleotides corresponding to either rs17373080 allele bound NF1 transcription factors in whole cell extracts to the same extent. Different NF1 family members showed different capacity to transactivate the LXRB gene promoter, but there was no difference between promoter alleles in NF1 induced transactivation activity.
Conclusion
Variations in the LXRB gene promoter may be part of the aetiology of T2D. However, the association between LXRB rs35463555 and rs17373080, and T2D are preliminary and needs to be investigated in additional larger cohorts. Common genetic variation in LXRA is unlikely to affect the risk of developing T2D or quantitative phenotypes related to glucose homeostasis.
doi:10.1186/1471-2350-10-27
PMCID: PMC2664799  PMID: 19292929
23.  Evaluation of the association between the common E469K polymorphism in the ICAM-1 gene and diabetic nephropathy among type 1 diabetic patients in GoKinD population 
BMC Medical Genetics  2008;9:47.
Background
The ICAM-1 gene is a strong positional and biological candidate for susceptibility to the development of T1D and DN. We have recently demonstrated that SNP rs5498(E469K) confers susceptibility to the development of T1D and might be associated with DN in Swedish Caucasians. The present study aimed to further evaluate the association between the ICAM-1 genetic polymorphisms and DN.
Methods
Two common non-synonymous SNPs, including rs5498(E469K) and rs1799969(R241G), in the ICAM-1 gene were genotyped in 662 (312 female/350 male) T1D patients with DN and 620 (369/251) without DN. All patients were selected from the GoKinD study.
Results
Genotype distributions of both SNPs were in Hardy-Weinberg equilibrium but SNP rs5498(E469K) had high heterozygous index. In this SNP, the heterozygosity and positivity for the allele G were found to be significantly associated with DN in female T1D patients (P = 0.010, OR = 0.633, CI 95% 0.447–0.895 and P = 0.026, OR = 0.692, CI 95% 0.500–0.958). Furthermore, the female patients without DN carrying three genotypes A/A, A/G and G/G had different cystatin levels (0.79 ± 0.17, 0.81 ± 0.14 and 0.75 ± 0.12 mg/L, P = 0.021). No significant association of SNP rs1799969 (R241G) with DN was found.
Conclusion
The present study provides further evidence that SNP rs5498(E469K) in the ICAM-1 gene presents a high heterozygous index and the allele G of this polymorphism may confers the decreased risk susceptibility to the development of DN in female T1D patients among the GoKinD population.
doi:10.1186/1471-2350-9-47
PMCID: PMC2424038  PMID: 18505543

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