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3073.Full.Pdf ORIGINAL ARTICLE Genetic Examination of SETD7 and SUV39H1/H2 Methyltransferases and the Risk of Diabetes Complications in Patients With Type 1 Diabetes Anna Syreeni,1 Assam El-Osta,2 Carol Forsblom,1,3 Niina Sandholm,1 Maikki Parkkonen,1 Lise Tarnow,4 Hans-Henrik Parving,5 Amy J. McKnight,6 Alexander P. Maxwell,6 Mark E. Cooper,2 and Per-Henrik Groop,1,2,3 on behalf of the FinnDiane Study Group OBJECTIVE—Hyperglycemia plays a pivotal role in the de- velopment and progression of vascular complications, which are the major sources of morbidity and mortality in diabetes. icro- and macrovascular complications develop Furthermore, these vascular complications often persist and in a subset of individuals with type 1 diabetes. progress despite improved glucose control, possibly as a result of The severity of comorbid complications is es- fi prior episodes of hyperglycemia. Epigenetic modi cations mediated pecially striking in patients with established by histone methyltransferases are associated with gene-activating M events that promote enhanced expression of key proinflammatory diabetic nephropathy, who have an 18.3-fold increased all- molecules implicated in vascular injury. In this study, we inves- cause mortality rate when compared with the general pop- tigated genetic polymorphisms of the SETD7, SUV39H1, and ulation (1). Diabetic nephropathy clusters in families (2), SUV39H2 methyltransferases as predictors of risk for micro- and which emphasizes the importance of an inherited genetic macrovascular complications in type 1 diabetes. component. Diabetic retinopathy is another microvascular — complication that has an inherited susceptibility (herita- RESEARCH DESIGN AND METHODS In the Finnish Di- h2 abetic Nephropathy Study (FinnDiane) cohort, 37 tagging single bility of = 0.52 in the Finnish population) (3). nucleotide polymorphisms (SNPs) were genotyped in 2,991 indi- Along with a genetic background, the lifetime glucose viduals with type 1 diabetes and diabetic retinopathy, diabetic exposure increases the risk of diabetes complications. In nephropathy, and cardiovascular disease. Seven SNPs were geno- the follow-up of the Diabetes Control and Complications typed in the replication cohorts from the Steno Diabetes Center Trial, known as the Epidemiology of Diabetes Interventions and All Ireland/Warren 3/Genetics of Kidneys in Diabetes (GoKinD) and Complications (EDIC) study, patients with conven- U.K. study. tional blood glucose control were more prone to diabetes RESULTS—In a meta-analysis, the minor T allele of the exonic than patients with intensive glucose control (4). Data from SNP rs17353856 in the SUV39H2 was associated with diabetic the EDIC and other clinical trials, including the UK Pro- 2 retinopathy (genotypic odds ratio 0.75, P = 1.2 3 10 4). The same spective Diabetes Study (5), indicate that diabetes com- SNP showed a trend toward an association with diabetic ne- plications continue to develop and progress even in phropathy as well as cardiovascular disease in the FinnDiane individuals who have managed to improve their glycemic cohort. control, a phenomenon referred to as hyperglycemic mem- CONCLUSIONS—Our findings propose that a genetic variation ory or the legacy effect. Epigenetic modifications on the in a gene coding for a histone methyltransferase is protective DNA and histone proteins represent potential mechanisms for a diabetic microvascular complication. The pathophysiolog- to explain the hyperglycemic memory (6). ical implications of this polymorphism or other genetic variation In a series of recent experimental studies, it was demon- nearby for the vascular complications of type 1 diabetes remain fi to be investigated. Diabetes 60:3073–3080, 2011 strated that hyperglycemia can induce speci c and long-lasting gene-activating epigenetic changes. In particular, transient hyperglycemia mediates specificchangestohistone3lysine 4 (H3K4) and lysine 9 (H3K9) (7,8). In human vascular cells previously exposed to hyperglycemia, the nuclear factor-kB (NF-kB) subunit RELA (alias p65) gene expression is in- creased partly as a result of monomethylation of H3K4 From the 1Folkhälsan Institute of Genetics, Folkhälsan Research Center, Bio- (H3K4me1) and decreased di- and trimethylation of H3K9 medicum Helsinki, Helsinki, Finland; the 2Epigenetics in Human Health and (H3K9me2 and H3K9me3) in the gene promoter. This Disease Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, RELA 3 upregulation of gene expression with concomitant Victoria, Australia; the Department of Medicine, Division of Nephrology, k fl Helsinki University Central Hospital, Helsinki, Finland; the 4Steno Diabetes NF- B activation results in increased expression of in amma- Center, Gentofte, Denmark; the 5Department of Medical Endocrinology, tory genes such as VCAM1 and MCP1 downstream in the Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark; and same pathway. Activated NF-kB has also been detected in a the 6Nephrology Research Group, Queen’s University of Belfast, Belfast, Northern Ireland, U.K. variety of renal cell types in patients with diabetic nephropathy Corresponding author: Per-Henrik Groop, per-henrik.groop@helsinki.fi. as well as in retinal pericytes in diabetic conditions (9,10). Received 21 January 2011 and accepted 11 July 2011. The gene coding for a histone methyltransferase for H3K4 DOI: 10.2337/db11-0073 This article contains Supplementary Data online at http://diabetes is the SET domain containing lysine methyltransferase 7 .diabetesjournals.org/lookup/suppl/doi:10.2337/db11-0073/-/DC1. (SETD7). The SETD7 protein is also a regulator of DNA Ó 2011 by the American Diabetes Association. Readers may use this article as (cytosine-5-)-methyltransferase 1 (DNMT1), which is re- long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by sponsible for maintaining DNA methylation patterning in -nc-nd/3.0/ for details. cell divisions (11). Suppressor of variegation 3–9 homolog 1 diabetes.diabetesjournals.org DIABETES, VOL. 60, NOVEMBER 2011 3073 SETD7 AND SUV39Hs IN TYPE 1 DIABETES COMPLICATIONS (SUV39H1) is a histone methyltransferase that catalyzes Clinical examination. Blood pressure was measured twice, and the average the methylation of H3K9, which is associated with the was calculated. Mean arterial pressure (MAP) was estimated from systolic blood suppression of transcription. SUV39H2 is another H3K9- pressure (SBP) and diastolic blood pressure (DBP) measurements. Height and weight were measured and BMI was calculated. Current smoking was defined as selective methyltransferase that shares strong sequence smoking at least one cigarette per day. The estimated glomerular filtration rate homology with SUV39H1. On the basis of previous experi- (eGFR) was calculated using the CKD-EPI (Chronic Kidney Disease Epidemi- mental studies, it appears that these enzymes (SETD7 and ology Collaboration) equation (12). A blood sample was obtained to determine SUV39H1/H2) are playing a pivotal role in the glucose- A1C and serum lipids and for DNA extraction. A1C was measured by stan- mediated inflammatory response and are therefore candi- dardized immunoassays. Serum lipids and lipoprotein concentrations were date genes for diabetic vascular complications, conditions measured by automated enzymatic methods. fl Replication populations. Danish patients with type 1 diabetes were recruited where chronic in ammation is often observed. from the Steno Diabetes Center. Diabetic nephropathy was defined as macro- In this study, genetic variation of SETD7 (chr4q31.1), albuminuria or ESRD and no other kidney disease. Altogether, 452 case subjects SUV39H1 (chrXp11.23), and SUV39H2 (chr10p13) was with diabetic nephropathy and 432 control subjects with normal AER and di- studied in relation to micro- and macrovascular compli- abetes duration $15 years were included. Diabetic retinopathy was graded as cations in a large well-characterized population of Finnish nil, simplex, or proliferative retinopathy, and patients with proliferative reti- patients with type 1 diabetes. Selected single nucleotide nopathy were compared with patients with no retinopathy. Cardiovascular events studied were stroke and myocardial infarction. Clinical characteristics of polymorphisms (SNPs) were genotyped in replication cohorts the Steno cohort are presented in Table 2. from the Steno Diabetes Center and All Ireland/Warren The other replication population was recruited as part of the All Ireland/ 3/Genetics of Kidneys in Diabetes (GoKinD) U.K. study. Warren 3/GoKinD U.K. resources, previously described elsewhere (13), and referred to as the GoKinD U.K. cohort in this article. In brief, 718 case subjects with diabetic nephropathy and 749 control subjects with no renal disease were RESEARCH DESIGN AND METHODS included. Retinopathy data were self-reported; 556 were case subjects with Discovery population. Patients were from the nationwide Finnish Diabetic proliferative retinopathy and 382 were control subjects (Table 2). Nephropathy Study (FinnDiane). At the baseline visit, patients underwent The study protocol was approved by the ethics committees of all participating a thorough clinical investigation in conjunction with a regular visit to the at- FinnDiane centers, a local ethical committee in Denmark, and research ethics tending physician. A total of 2,991 patients with type 1 diabetes were included. committees in the U.K. and Ireland. The protocol follows the Declaration of Type 1 diabetes
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