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Diabetic nephropathy (DN) is a ruining complicationof type 1 and type 2 diabetes and leads to increasedmorbidity and premature mortality.Diabetes and nephropathy are the leading causes of end stage renal disease (ESRD) and Diabetic kidney disease (DKD) and is a life-threatening and irreversible decline in renal function. Population studies have also shown that parents of individuals with diabetic nephropathy is more susceptible to hypertension,cardiovascular and cerebrovascular disease associated withearly mortality. Parental type 2 diabetes mellitus increases the risk of diabetic nephropathy in offspring with type 1 diabetes mellitus. The prevalence of patients with Diabetes Miletus worldwide was estimated at 173 million in 2002 and is predicted to increase to 350 million cases by 2030 reported by World Health Report (2006).
In Saudi Arabia, the summarized estimate of DN prevalence is 31.41% in the western region, 29.15% in the eastern region, and 24.98% in the central region [Amal 2012]. This endemicity is believed to be due to recent socio-economical changes in these areas.
Since cumulative epidemiological findings have providedevidence that genetic susceptibility plays an importantrole in the pathogenesis of diabetic nephropathy, and it efforts to identify the genes involved in the developmentand progression of diabetic nephropathy in both type 1and type 2 diabetes has beenwidespread, but nodefinitive results have yet emerged.
The candidate gene approach involvingassessment of genetic variant's studies in characteristically SNPs, in genes with possible physiological roles in DN.successful candidate genes are protein kinase C βgene (PRKCB) associatedwithT2D nephropathy, a SNP in theerythropoietin gene(EPO) promoter associatedwith proliferative diabetic retinopathy and endothelial nitric oxide synthase gene (NOS3) associatedwithDN.Based on literature searches, genetic association studies investigating DN were identified; 34 replicated genetic variants were identified with 21 significantly associated with DN in the meta-analysis, A complete gene list provided in Table 1.
We propose to perform the SNP array technology to screen the multi locus of the cases for SNPs over coding and non-coding regions indiabetic nephropathy cases, diabetic cases and controls derived from healthy Saudi individuals. We shall use the state-of-the-art SNP array technology Iscanplatform, Illumina already assembled at the PMCRCS, University of Dammam. Furthermore, PCR technique (Taqman assay / sequencing) will be utilized to reconfirm thecandidate SNPs. We shall employ the ABI prism /Illumina next generation sequence platform for sequencing the PCR products.
Previous studies have been typically abortive to achieve satisfactory performance, primarily due to the use of only a limited number of confirmed susceptibility loci. Consequently,this study is of paramount importance to improve the health status of at-risk population in the Eastern Province.
Nephropathy intends kidney disease or damage. Diabetic nephropathy is destruction to kidneys caused by diabetes,in severe cases it can lead to death.Diabetic nephropathy affects 30-40% of the patients with type 1 and type 2 diabetes; it leads to complicationssuch as kidney failure, non-traumatic leg amputations and adult-onset blindness in the western world [Gross 2005]. Diabetic nephropathy is categorized into stages: micro-albuminuria (urinary albumin excretion >20µg/min) and macro-albuminuria (urinary albumin excretion >200 µg/min). Hyperglycemia levels,increased blood pressure levels and genetic predispositionare the main risk factors for the development of diabetic nephropathy [Gross 2005]. A various populationbased studywasperformedin Japanese and European population with the goal of detecting common genetic variation associated with the disease of interest [Freedman 2007],but current GWAS arrays studies are not as informative in non-European-derived populations.
Current data indicates that at least 6% of the world's population is affected, with the worldwide prevalence reaching 12% by 2025 [Zimmet 2001],and is now considered among one of the highest in the world with prevalence between 9.7% and 23.7%.In Saudi Arabia the prevalence of Diabetes Miletus from the past two decades dramatically increased. The prevalence of diabetes mellitus (DM) in the Saudi Arabia population is high and 90% of diabetics suffer from Type II DM. An epidemiological study of Saudi Arabia subjects aged 15 years or older, from different regions of the kingdom found that the ageâ€adjusted prevalence of diabetes mellituswas higher in urban areas than rural areas(Saudi Center for Organ Transplantation 2006).In Saudi Arabia the run throughestimate of DN prevalence is 31.41% in the western region, 29.15% in the eastern region, and 24.98% in the central region [Amal 2012]. This endemicity is believed to be due to recent socio-economical changes in the area.Diabetic nephropathy occurs in 24% of Saudi Arabian diabetes patients, and it accounts for 45% of the causes of chronic kidney disease [Alwakeel2002].
Genes that predispose to diabetic nephropathy also predispose to type 2 diabetes. Such subjects had a greater risk of diabetes if their type 2 diabetic parents had established nephropathy, compared to those whose parents had diabetes without nephropathy. A parental history of type 2 diabetes is associated with increased risk of proteinuria in type 1 diabetic patients [Freedman 1995]. On the otherpart, nonâ€diabetic offspring of diabetic patients with nephropathy have a higher albumin excretion rate compared to nonâ€diabetic offspring of diabetic patients without nephropathy[Agius 2006]. The offspring of a parent with diabetes have a lifetime risk of40% fortype 2 diabetes and when both parents have to type 2diabetes, the risk is even higher.Parental type 2 diabetes mellitus increases the risk of diabetic nephropathy in offspring with type 1 diabetes mellitus [Fagerholm 2012].
GWAS for T2DM-ESRD in African Americans studies are revealed 25 potential variants in 19 genes associated with T2DM -ESRD including: SASH1, AUH, MSRB3-HMGA2, RPS12, and LIMK2-SFI1 [McDonough 2011].Previously Identified Nephropathy Geneshave been implicated in different ethnicities with either renal failure or renal function in both diabetics and non-diabetics association with many of these genes FRMD3, CARS, SLC22A2, PRKAG2, ACACB, NEDD4L, CNDP1, CNDP2, ELMO1, SERPINB7, SHROOM3, UMOD, GATM-SPATA5L1, GCK2, ALMS1, DAB2, SLC34A1, PVT1, VEGFA, STC1, ATXN2, DACH1, SLC7A9 [McDonough 2011].Table 1
In 2011, the first GWAS of DN in African Americans was performed using 965 T2D patientswith end-stage renal disease (ESRD) and 1,029 controls without diabetes or nephropathy [McDonough 2011].TheSNP loci indicated a geneencoding solute carrier family12 member 3 (SLC12A3) to be a good candidate for the susceptibility to diabetic nephropathy[Tanaka 2003].Diabetic nephropathy is more prevalent among African Americans, Asians, and Native Americans than Caucasians, revealedmultiple common variants in MYH9associated with up to 7-fold risk for non-diabetic ESRD and focal segmental glomerulosclerosis, thus explaining most of the excess risk for these diseases in African Americans[Kao 2008]. A genome-wide association study for diabetic nephropathy in African Americans identified genes such asRPS12, LIMK2, and SFI1 asstrongcandidates for diabetic nephropathy[McDonough 2011].The candidate gene approach involves assessment of genetic variant's studies in DN, andsuccessful candidate genes are the protein kinase C β gene (PRKCB) association in T2D nephropathy, a SNP in the erythropoietin gene (EPO) promoter withproliferatives diabetic retinopathy and endothelial nitric oxide synthase gene (NOS3) association in Diabetic Nephropathy[Nicholette2012].in type 2 diabetes in Chinese individualsa common variantsfrom NOX4 and endothelin-1 were associated with differentialplasma Cu/Zn SOD and C-terminal pro-endothelin-1concentrations[ Lim 2009].
Association studiesof coronary artery disease with single nucleotide polymorphisms in diabetic nephropathy was performed.One SNP on chromosome 19q13 wasfound to be significantly associated with diabetic nephropathy [McKnight 2009]. a Obesity,influencefor the continued increase in the prevalence of type 2 diabetes and they interact and contribute to diabetic nephropathy;[Ogden 2006, Mohammad 2010].The advanceof diabetic nephropathy is commonly believedto result from the collectiveinteractions among multiple metabolic and hemodynamic factors, which activate common intracellular signaling pathways that in turn trigger the production of cytokines and growth factors, leading to kidney disease [Christine Maric 2011] and developmentin Glomerular Filtration Rate (GFR) investigates the potential risk factors associated with progression to Diabetic Nephropathy among Saudi patients [Jamal 2011].
Microarrays make use of SNP detection, including genotyping, genetic linkage analysis and identifying mutations in individuals with the development of high density SNP arrays and identify loci that contributes to type 2 diabetes mellitus by GWAS and replication population studies in multiple African-American samples [Palmer2012].The first GWAS for Diabetic nephropathy was performed in a Japanese population using a low- density array genotyping ~80,000gene-based SNPs [Nicholette2012].
In Saudi Arabia studies on diabetic complications conducted in Saudi Arabia are very few [Abdullah 2001]. Insight into the genetic aspects has been not be initiated in the kingdom. Thus, the present study is a pilot approach and is of key importance to the Saudi population.The state-of-the-art array SNP technology Iscan, Illumina platform will be use and Illumina next generation sequence platform for sequencing the PCR products.
Identifying mutations in individuals with the development of high density SNP arrays and identify a locus that contributes toDiabetic Nephropathy byMicroarrays of SNP detection.Our aim of the large project is to develop and apply diabetic and diabetic nephropathy specific arrays which interrogate SNPs and genes related to diabetic and diabetic nephropathy and drug response. The results should function as risk assessors for diabetic nephropathy and will promote in further personalized medicine approaches. This kind of clinical genetic approach becomes realistic, in view of treatment options that can become more predictable when genetic causes are specified.
Involvement of students and young researchers in the project will contribute to the transfer of knowledge and technology to the local population and will contribute to postgraduate programs.
The investigators of this project at the University of Dammam will work in close collaboration with participating centers in the Eastern Province and Utrecht Medical Complex and University of Pennsylvania, thereby facilitating interaction between all institutes involved in the project. This collaboration is economically logical to safeguard the funds required for research within the Kingdom by reducing unnecessary expenses and duplication of expensive equipment.
This is a project submitted for funding and we believe that it deals with an important issue. Diabetic Nephropathy is a disease prevalent in the Eastern Province, which has health and socio-economical impacts. Therefore in summation, this project has the following characteristics: