Critical Association Study of Olfactory Receptor Gene Polymorphism in Diabetic Complications
Mohamed Jahromi1,2*, Adel Ahmed2,3, Kazem Behbehani2 and Anwar Mohammad2
1Pathology Department, Salmaniya Medical Complex, Bahrain
2Dasman Diabetes Institute, Dasman, Kuwait
3Faculty of Medicine, Health Science Center, Kuwait University, Kuwait
- Corresponding Author:
- Mohamed M Jahromi
Senior Clinical Scientist,Transitional Research Group
Clinical Research Unit, Directorate of Clinical Services
Dasman Diabetes Institute, P.O Box 1180, Dasman 15462, Kuwait
E-mail: [email protected]
Received date: August 04, 2014; Accepted date: September 29, 2014; Published date: October 01, 2014
Citation: Jahromi M, Ahmed A, Behbehani K, Mohammad A (2014) Critical Association Study of Olfactory Receptor Gene Polymorphism in Diabetic Complications. Immunome Res 10:079. doi:10.4172/17457580.1000079
Copyright: © 2014 Jahromi M et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Type I diabetes (TID) is an autoimmune disease (AD) known to trigger retinopathy, neuropathy and nephropathy. Recent findings suggest that numerous pathways are activated during the course of T1D and that these pathways individually or collectively influence progression to Diabetic Nephropathy (DN).
A single nucleotide polymorphism (SNP) in the promoter region of the Olfactory Receptor family 14 (OR14) gene, rs9257691, has been shown to be significantly associated with T1D in general. Recent investigations have emphasized on the significance of OR in diabetic complications. In this pilot study, we sought to confirm these findings by investigating the OR14 gene in a group of patients with and without diabetic complications. A hundred patients with (n=75) and without (n=25) different diabetic complications (i.e. Retinopathy (DR), Neuropathy (DNu) and DN) were recruited. Patients with long term ≥ 20 years history of diabetes with no complications were considered as the control group. Case and control subjects were genotyped for OR14 gene adjacent to the Human Leukocyte Antigen (HLA)-F region.
The current results showed that the OR14-CC genotype is more significant in patients with DN, p=0.004, in comparison to groups with other complications. No other statistically significant difference was found among male and female groups. In addition, there was no difference in allelic frequencies of cases compared to control subjects.
This critical analysis indicates that patients with T1D who have the OR14-CC genotype are significantly
susceptible to progressive DN. Screening and identifying diabetic patients at risk for future nephropathy would permit better clinical management. However, a large scale association study is recommended to confirm the above findings.
Diabetic nephropathy; Olfactory receptor gene; Diabetic complications; MHC-X gene
AD is defined when the progression from benign autoimmunity to pathogenic autoimmunity occurs; such as T1D . In the case of T1D secondary diseases are manifested such as DR, DNu and DN [2,3]. The aforementioned secondary complications are also found in type-2- diabetes (T2D), however, they are more serious in T1D [4-6].
T1D is an AD that is caused by the destruction of the insulinproducing pancreatic β-cells. Several factors may contribute to the pathogenesis of T1D; accumulative evidence suggest that both genetic and environmental factors contribute to the etiology of T1D . Genetic susceptibility of T1D has been determined by studying polymorphisms in multiple genes in both human and animal models . In this regard, Genome Wide Association Studies (GWAS) indicate that the highly polymorphic Major Human Complex (MHC), including both MHC class I and class II, contribute to approximately 50% of genetic susceptibility to T1D [8-13].
According to the recent GWAS there are 60 non-MHC genes or loci associated with the disease , out of which 45 are immune related genes . We have also reported a significant association of genes, both MHC and MHC-linked (MHC-x), with T1D [14,15].
OR genes are the largest gene family in the human genome comprising ~400 genes and ~600 pseudogenes [16-18]. Ignatieva and coworkers have recently conducted a novel analysis on SNPs using GWAS data from 1000 Genome Projects and revealed an extremely high level of SNPs in the promoter regions of the OR and HLA genes. The extremely high level of SNP content in promoters of OR genes raise the question about the functional significance of such SNPs for olfactory cognition as well as their association with human diseases . The study provided strong genetic confirmation for already existing reports about the unique appearance of OR that is inextricably related to immunological function [20-22]. In addition, it might be an interesting genetic reasoning for the accumulative evidence that OR dysfunction exists in brain diseases such as Multiple Sclerosis [23-29], Alzheimer Disease [27,28,30-32], Parkinson’s Disease [27,28,33-37], and depression [38-44].
OR14 gene is located in the telomeric region of HLA-F  where an interesting haplotype-specific association between T1D and a SNP in the promoter region of OR14 gene, rs9257691, has been reported .
The association of olfaction has been reported in diabetic complications since 1993, and has also been associated with degenerative complications of T1D [45,46]. There is accumulating evidence that glucose-induced oxidative stress plays a role in diabetic complications, and that OR plays an important role in their pathogenesis [47-50]. Meanwhile, studies have shown an association between OR impairment in diabetic ketoacidosis and encephalopathy [51-55], neuropathy , retinopathy [56-58] and nephropathy [58-61]. Therefore, the present study aims to further our current understanding of the significance of the SNP in the promoter region of the OR14 gene in the pathobiology of T1D and its associated complications.
Materials and Methods
This pilot study comprised of 100 Europid Caucasoid patients with T1D, as defined by the National Diabetes Data Group, and 25 patients of them were considered as Diabetic Control (DC) for the complication study [62-67] (Table 1).
|| Number of Patients
|| 14 13
|| 9 11
|| 13 15
|| 12 13
Table 1: Distribution of cases and control subjects enrolled in the study.
DR=patients with retinopathy; identified as having more than 5 blots per eye: hard or soft exudates, new vessels or flourescein angiographic evidence of maculopathy or previous laser treatment for preproliferative or proliferative retinopathy.
DNu= patients with overt neuropathy; identified by the presence of ankle jerk loss, sensations of pain, foot ulcer and/or autonomic neuropathy.
DN= patients with nephropathy; identified as having had diabetes for more than 10 years with persistent proteinuria over 12 months in the absence of hematuria or infection.
DC= patients who have had diabetes for at least 20 years but remain free of retinopathy and proteinuria.
Microvascular complications included Diabetic Neuropathy [DNe (nerve damage)], Diabetic Retinopathy [DR (e.g. glaucoma, cataract, and corneal disease)], and Diabetic Nephropathy [DN (kidney disease)]. Patients with overt DNe were identified by the presence of ankle jerk loss, sensations of pain, foot ulcer, and/or autonomic neuropathy. Patients with retinopathy were identified as having more than five blots per eye: hard or soft exudates, new vessels or flourescein angiographic evidence of maculopathy, or previous laser treatment for preproliferative or proliferative retinopathy. Patients with nephropathy were identified as having had diabetes for >10 years with persistent proteinuria over a 12 month period in the absence of hematuria or infection. Patients who have had diabetes for at least 20 years but remain free of retinopathy and nephropathy were considered as Diabetic Control (DC) as previously explained . Although cardiovascular disease is more prevalent among patients with T1D (as well as type 2 diabetes) than those without; in this study, cardiovascular disease was not considered as a diabetes-specific complication [68-71].
The case and control subjects were genotyped for the OR14 gene polymorphism using Taqman SNP genotyping (Applied Biosystems) as discussed previously .
The frequency of the OR14 genotypes met the Hardy-Weinberg principle. The Fisher’s 2-sided exact test was used to compare allele and genotype frequencies of A-OR14-C in the entire group of cases (n=75) against diabetic controls (n=25).
There was a critical and significant association among the OR14- CC genotype in patients who developed DN, p=0.004, but no statistically significant differences were noted in cases of DR, p=0.23, or DNu, p=0.09, compared to DC (Table 2).
Table 2: Association of the OR SNP among diabetic complication groups.
A comparison between the OR-CC among all diabetic complication groups (ie DR, DNU as well as DN) showed that OR-CC is critically associated with DN, p=0.004.
However, neither of DR or DNu cases meet statistical significance, p=0.23 and p=0.09 respectively. The OR-CC distribution among male and female groups also did not show any significant difference.
There were no other significant differences among gender of patients with diabetic complications compared to DC, and no significant differences in allelic comparisons among diabetics with complications compared to DC groups.
Complications of T1D are secondary conditions: DR, DNu and DN are disorders commonly associated with the disease and affect large populations worldwide .
The current findings suggest that OR14-CC genotype of A-OR14-C SNP (rs9257691), in the telomeric region of HLA-F, is significantly associated with DN but not DR or DNu in comparison to DC.
Emerging evidence indicate that different genetic and environmental factors play a role in the regulation of inflammatory and profibrotic genes in renal and vascular cells under diabetic conditions which lead to DN . Further, accumulative evidence state that DN develops in 20-25% of patients with T1D .
Recently, Gascón et al., have reported an interesting finding that the olfactory function test is an indicator of early microvascular complications in diabetic patients . On the other hand, Pluznick et al. have clearly stated that the olfactory system may play a physiologically critical role in regulating fundamental aspects of renal function . Further, Ignatieva et al. findings of SNPs in promoter regions of ORs raised the question about the functional significance of coding SNPs for OR as well as about their association with human diseases . The current finding provides genetic back up for the above investigations; that OR14-CC could be used as a valuable marker to indicate the presence of mechanisms that play a role in the progression of DN in T1D. T1D and DN still present considerable challenge globally with DN being the most frequent reason for dialysis in many Western countries . Therefore, the detection of a DN marker in the early onset of T1D might be of therapeutic value, thereby postponing and/or preventing the need for renal replacement therapy. Our results confirm the novel findings of Gascón et al. who have recently addressed the usefulness of smell test renal dysfunction . Therefore, it is important to further this study in a large multicenter investigation of diabetic complications. Any screening test as such needs to be rigorously studied in both adult and pediatric populations before any universal screening is recommended.
The critical association of the OR14-CC gene with DN patients might be a good marker for early prognoses of DN during early onset of T1D
Detection of a DN marker in the early onset of T1D might be of therapeutic value, thereby postponing and/or preventing the need for renal replacement therapy
This study indicates that patients with T1D who have the OR14-CC genotype are significantly susceptible to progressive DN
It is recommended to run confirmatory multicenter investigation for the OR-CC association with DN before establishing screening test
This work was not supported by specific grants. However, we would like to express our sincere thanks to Amal Hasan for her fruitful revision. As we would like to appreciate Dr John Todd at Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute of Medical Research, University of Cambridge, UK and late Dr George Eisenbarth the ex-executive director of Barbara Davis Center for Diabetes Study, University of Colorado Health Sciences Center, University of Colorado, Denver, USA for his continuous support and encouragements and mentorship
- Anaya JM (2012) Common mechanisms of autoimmune diseases (the autoimmune tautology) Autoimmun Rev 11: 781-784.
- Agmon-Levin N, Shoenfeld Y (2014) The spectrum between antiphospholipid syndrome and systemic lupus erythematosus ClinRheumatol 33: 293-295.
- Harel M, Shoenfeld Y (2006) Predicting and preventing autoimmunity, myth or reality? Ann N Y AcadSci 1069: 322-345.
- Uruska A, Araszkiewicz A, Uruski P, Zozulinska-Ziolkiewicz D (2014) Higher risk of microvascular complications in smokers with type 1 diabetes despite intensive insulin therapy Microvasc Res 92: 79-84.
- Assogba FG, Couchoud C, Hannedouche T, Villar E, Frimat L, et al. (2014) Trends in the epidemiology and care of diabetes mellitus-related end-stage renal disease in France, 2007-2011. Diabetologia 57: 718-728.
- Miao F, Chen Z, Genuth S, Paterson A, Zhang L, et al. (2014) Evaluating the role of epigenetic histone modifications in the metabolic memory of type 1 diabetes Diabetes 63: 1748-1762.
- International Diabetes Federation-UN Resolution 61/225 (2013) 6th edition.
- Jahromi MM, Eisenbarth GS (2006) Genetic determinants of type 1 diabetes across populations Ann N Y AcadSci 1079: 289-299.
- Carp HJ, Selmi C, Shoenfeld Y (2012) The autoimmune bases of infertility and pregnancy loss J Autoimmun 38: J266-274.
- Zhou Z, Jensen PE (2013) Structural Characteristics of HLA-DQ that May Impact DM Editing and Susceptibility to Type-1 Diabetes Front Immunol 4: 262.
- Noble JA, Valdes AM, Varney MD, Carlson JA, Moonsamy P, et al. (2010) HLA Class I and Genetic Susceptibility to Type 1 Diabetes Results From the Type 1 Diabetes Genetics Consortium. Diabetes; 59:2972-2979.
- Nokoff NJ, Rewers M, Cree Green M (2012) The interplay of autoimmunity and insulin resistance in type 1 diabetes Discov Med 13: 115-122.
- Pociot F, Akolkar B, Concannon P, Erlich HA, Julier C, et al. (2010) Genetics of Type 1 Diabetes: What’s Next? Diabetes 59: 1561-1571.
- Bakay M, Pandey R, Hakonarson H (2013) Genes involved in type 1 diabetes: an update Genes (Basel) 4: 499-521.
- Jahromi MM (2012) Haplotype specific alteration of diabetes MHC risk by olfactory receptor gene polymorphism Autoimmun Rev 12: 270-274.
- Aly TA, Baschal EE, Jahromi MM, Fernando MS, Babu SR, et al. (2008) Analysis of single nucleotide polymorphisms identifies major type 1A diabetes locus telomeric of the major histocompatibility complex Diabetes 57: 770-776.
- Firestein S (2001) How the olfactory system makes sense of scents Nature 413: 211-218.
- Hasin Y, Olender T, Khen M, Gonzaga-Jauregui C, Kim PM, et al. (2008) High-resolution copy-number variation map reflects human olfactory receptor diversity and evolution PLoS Genet 4: e1000249.
- Olender T, Waszak SM, Viavant M, Khen M, Ben-Asher E, et al. (2012) Personal receptor repertoires: olfaction as a model BMC Genomics 13: 414.
- Ignatieva EV, Levitsky VG, Yudin NS, Moshkin MP, Kolchanov NA (2014) Genetic basis of olfactory cognition: extremely high level of DNA sequence polymorphism in promoter regions of the human olfactory receptor genes revealed using the 1000 Genomes Project dataset. Front Psychol 5: 247.
- Bernstein JA, Zhang G, Jin L, Abbott C, Nebert DW (2008) Olfactory receptor gene polymorphisms and nonallergic vasomotor rhinitis J Asthma 45: 287-292.
- Kivity S, Ortega-Hernandez OD, Shoenfeld Y (2009) Olfaction--a window to the mind Isr Med Assoc J 11: 238-243.
- Spehr M, Munger SD (2009) Olfactory receptors: G protein-coupled receptors and beyond J Neurochem 109: 1570-1583.
- Doty RL, Li C, Mannon LJ, Yousem DM (1999) Olfactory dysfunction in multiple sclerosis: relation to longitudinal changes in plaque numbers in central olfactory structures Neurology 53: 880-882.
- Burfoot RK, Jensen CJ, Field J, Stankovich J, Varney MD, et al. (2008) SNP mapping and candidate gene sequencing in the class I region of the HLA complex: searching for multiple sclerosis susceptibility genes in Tasmanians Tissue Antigens 71: 42-50.
- Baranzini SE (2009) The genetics of autoimmune diseases: a networked perspective CurrOpinImmunol 21: 596-605.
- Ramos PS, Criswell LA, Moser KL, Comeau ME, Williams AH, et al. (2011) A comprehensive analysis of shared loci between systemic lupus erythematosus (SLE) and sixteen autoimmune diseases reveal limited genetic overlap. PLoS Genet 7: e1002406.
- Menon R, Farina C (2011) Shared molecular and functional frameworks among five complex human disorders: a comparative study on interactomes linked to susceptibility genes PLoS One 6: e18660.
- Guglielmetti C, Praet J, Rangarajan JR, Vreys R, De Vocht N, et al. (2014) Multimodal imaging of subventricular zone neural stem/progenitor cells in the cuprizone mouse model reveals increased neurogenic potential for the olfactory bulb pathway, but no contribution to remyelination of the corpus callosum. Neuroimage 86: 99-110.
- Foster J, Sohrabi H, Verdile G, Martins R (2008) Research criteria for the diagnosis of Alzheimer's disease: genetic risk factors, blood biomarkers and olfactory dysfunction IntPsychogeriatr 20: 853-855.
- Shaw CA, Li Y, Wiszniewska J, Chasse S, Zaidi SN, et al. (2011) Olfactory copy number association with age at onset of Alzheimer disease Neurology 76: 1302-1309.
- Doty RL, Kamath V (2014) The influences of age on olfaction: a review Front Psychol 5: 20.
- Benkler M, Agmon-Levin N, Shoenfeld Y (2009) Parkinson's disease, autoimmunity, and olfaction Int J Neurosci 119: 2133-2143.
- Teixeira CS, Oliveira DL, Momeni P, Lees A, Hardy J, et al. (2009) Familial Parkinsonism and early onset Parkinson's disease in a Brazilian Movement Disorders Clinic: phenotypic characterization and frequency of SNCA, PRKN, PINK1 and LRRK2 mutations. MovDisord 24: 662-666.
- Chang XL, Mao XY, Li HH, Zhang JH, Li NN, et al. (2011) Association of GWAS loci with PD in China Am J Med Genet B Neuropsychiatr Genet 156B: 334-339.
- Li X, Sundquist J, Sundquist K (2012) Subsequent risks of Parkinson disease in patients with autoimmune and related disorders: a nationwide epidemiological study from Sweden Neurodegener Dis 10: 277-284.
- Peeraully T, Tan EK (2012) Genetic variants in sporadic Parkinson's disease: East vs West Parkinsonism RelatDisord 18 Suppl 1: S63-65.
- Garcia-Esparcia P, Schlüter A, Carmona M, Moreno J, Ansoleaga B et al. (2013) Functional genomics reveals dysregulation of cortical olfactory receptors in Parkinson disease: novel putative chemoreceptors in the human brain. J NeuropatholExp Neurol. 72: 24-39.
- Strous RD, Shoenfeld Y (2006) To smell the immune system: olfaction, autoimmunity and brain involvement Autoimmun Rev 6: 54-60.
- Katzav A, Solodeev I, Brodsky O, Chapman J, Pick CG, et al. (2007) Induction of autoimmune depression in mice by anti-ribosomal P antibodies via the limbic system Arthritis Rheum 56: 938-948.
- Moscavitch SD, Szyper-Kravitz M, Shoenfeld Y (2008) Autoimmune pathology accounts for common manifestations in a wide range of neuro-psychiatric disorders: The olfactory and immune system interrelationship. ClinImmunol 130: 235-243.
- Ortega-Hernandez OD, Kivity S, Shoenfeld Y (2009) Olfaction, psychiatric disorders and autoimmunity: is there a common genetic association? Autoimmunity 42: 80-88.
- Shoenfeld N, Agmon-Levin N, Flitman-Katzevman I, Paran D, Katz BS, et al. (2009) The sense of smell in systemic lupus erythematosus Arthritis Rheum 60: 1484-1487.
- Shoenfeld Y (2009) Olfactory defects point to nervous system involvement in lupus. The Rheumatologist 3: 15-17.
- Perricone C, Shoenfeld N, Agmon-Levin N, de Carolis C, Perricone R, et al. (2013) Smell and autoimmunity: a comprehensive review Clin Rev Allergy Immunol 45: 87-96.
- Weinstock RS, Wright HN, Smith DU (1993) Olfactory dysfunction in diabetes mellitus PhysiolBehav 53: 17-21.
- Le Floch JP, Le Lièvre G, Labroue M, Paul M, Peynegre R, et al. (1993) Smell dysfunction and related factors in diabetic patients Diabetes Care 16: 934-937.
- King GL, Loeken MR (2004) Hyperglycemia-induced oxidative stress in diabetic complications Histochem Cell Biol 122: 333-338.
- Cline GD, Schwartz DD, Axelrad ME, Anderson B (2011) A pilot study of acute stress symptoms in parents and youth following diagnosis of type I diabetes J ClinPsychol Med Settings 18: 416-422.
- Hoeldtke RD, Bryner KD, VanDyke K (2011) Oxidative stress and autonomic nerve function in early type 1 diabetes ClinAuton Res 21: 19-28.
- Molina-Jijón E, Rodríguez-Muñoz R, NamoradoMdel C, Pedraza-Chaverri J, Reyes JL (2014) Oxidative stress induces claudin-2 nitration in experimental type 1 diabetic nephropathy Free RadicBiol Med 72: 162-175.
- Sima AA (2010) Encephalopathies: the emerging diabetic complications ActaDiabetol 47: 279-293.
- Hoffman WH, Andjelkovic AV, Zhang W, Passmore GG, Sima AA (2010) Insulin and IGF-1 receptors, nitrotyrosin and cerebral neuronal deficits in two young patients with diabetic ketoacidosis and fatal brain edema. Brain Res 1343: 168-177.
- Guven A, Cebeci N, Dursun A, Aktekin E, Baumgartner M, et al. (2012) Methylmalonicacidemia mimicking diabetic ketoacidosis in an infant Pediatr Diabetes 13: e22-25.
- Fritsch M, Rosenbauer J, Schober E, Neu A, Placzek K, et al. (2011) Predictors of diabetic ketoacidosis in children and adolescents with type 1 diabetes. Experience from a large multicentre database Pediatr Diabetes 12: 307-312.
- Brady S, Lalli P, Midha N, Chan A, Garven A, et al. (2013) Presence of neuropathic pain may explain poor performances on olfactory testing in diabetes mellitus patients Chem Senses 38: 497-507.
- Huo SJ, Li YC, Xie J, Li Y, Raisman G, et al. (2012) Transplanted olfactory ensheathing cells reduce retinal degeneration in Royal College of Surgeons rats Curr Eye Res 37: 749-758.
- Grassi MA, Tikhomirov A, Ramalingam S, Below JE, Cox NJ, et al. (2011) Genome-wide meta-analysis for severe diabetic retinopathy Hum Mol Genet 20: 2472-2481.
- Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group (2000) Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med 342:381-389.
- Pluznick JL, Zou DJ, Zhang X, Yan Q, Rodriguez-Gil DJ, et al. (2009) Functional expression of the olfactory signaling system in the kidney ProcNatlAcadSci U S A 106: 2059-2064.
- Vettorazzi A, Wait R, Nagy J, Monreal JI, Mantle P (2013) Changes in male rat urinary protein profile during puberty: a pilot study BMC Res Notes 6: 232.
- Gascón C, Santaolalla F, Martínez A, Sánchez Del Rey A (2013) Usefulness of the BAST-24 smell and taste test in the study of diabetic patients: a new approach to the determination of renal function ActaOtolaryngol 133: 400-404.
- The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group (2005) Intensive Diabetes Treatment and Cardiovascular Disease in Patients with Type 1 Diabetes. N Engl J Med 353: 2643-2653.
- (1993) The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group N Engl J Med 329: 977-986.
- Lachin JM, Orchard TJ, Nathan DM; DCCT/EDIC Research Group (2014) Update on cardiovascular outcomes at 30 years of the diabetes control and complications trial/epidemiology of diabetes interventions and complications study Diabetes Care 37: 39-43.
- Jahromi MM, Millward BA, Demaine AG (2010) Significant Correlation Between Association of Polymorphism in Codon 10 of Transforming Growth Factor-ß1 T (29) C With Type 1 Diabetes and Patients With Nephropathy Disorder. J Interferon Cytokine Res 30: 59-66.
- Melendez-Ramirez LY, Richards RJ, Cefalu WT (2010) Complications of type 1 diabetes EndocrinolMetabClin North Am 39: 625-640.
- Zürbig P, Jerums G, Hovind P, Macisaac RJ, Mischak H, et al. (2012) Urinary proteomics for early diagnosis in diabetic nephropathy Diabetes 61: 3304-3313.
- Krolewski AS, Kosinski EJ, Warram JH, Leland OS, Busick EJ, et al. (1987) Magnitude and determinants of coronary artery disease in juvenile-onset, insulin-dependent diabetes mellitus Am J Cardiol 59: 750-755.
- Reddy MA, Natarajan R (2011) Epigenetic mechanisms in diabetic vascular complications Cardiovasc Res 90: 421-429.
- Theilade S, Hansen TW, Rossing P (2014) Central hemodynamics are associated with cardiovascular disease and albuminuria in type 1 diabetes Am J Hypertens 27: 1152-1159.