title: Meta-analysis of diabetic nephropathy associated genetic variants in inflammation and angiogenesis involved in different biochemical pathways.
abstract: BACKGROUND
  Diabetes mellitus is the most common chronic endocrine disorder, affecting an estimated population of 382 million people worldwide. It is associated with microvascular and macrovascular complications, including diabetic nephropathy (DN); primary cause of end-stage renal disease. Different inflammatory and angiogenic molecules in various pathways are important modulators in the pathogenesis and progression of diabetic nephropathy. Differential disease risk in DN may be partly attributable to genetic susceptibility. In this meta-analysis, we aimed to determine which of the previously investigated genetic variants in these pathways are significantly associated with the development of DN and to examine the functional role of these genes.
  
  
  METHODS
  A systematic search was conducted to collect and analyze all studies published till June 2013; that investigated the association between genetic variants involved in inflammatory cytokines and angiogenesis and diabetic nephropathy. Genetic variants associated with DN were selected and analyzed by using Comprehensive Meta Analysis software. Pathway analysis of the genes with variants showing significant positive association with DN was performed using Genomatix Genome Analyzer (Genomatix, Munich, Germany).
  
  
  RESULTS
  After the inclusion and exclusion criteria for this analysis, 34 studies were included in this meta-analysis. 11 genetic variants showed significant positive association with DN in a random-effects meta-analysis. These included genetic variants within or near VEGFA, CCR5, CCL2, IL-1, MMP9, EPO, IL-8, ADIPOQ and IL-10. rs1800871 (T) genetic variant in IL-10 showed protective effect for DN. Most of these eleven genetic variants were involved in GPCR signaling and receptor binding pathways whereas four were involved in chronic kidney failure. rs833061 [OR 2.08 (95% CI 1.63-2.66)] in the VEGFA gene and rs3917887 [OR 2.04 (95% CI 1.64-2.54)] in the CCL2 gene showed the most significant association with the risk of diabetic nephropathy.
  
  
  CONCLUSIONS
  Our results indicate that 11 genetic variants within or near VEGFA, CCR5, CCL2, IL-1, MMP9, EPO, IL-8, ADIPOQ and IL-10 showed significant positive association with diabetic nephropathy. Gene Ontology or pathway analysis showed that these genes may contribute to the pathophysiology of DN. The functional relevance of the variants and their pathways can lead to increased biological insights and development of new therapeutic targets.
authors.affiliation: Strategic Center for Diabetes Research, King Saud University, P.O. Box 18397, Riyadh, 11415, K.S.A, Saudi Arabia. npeerzada@ksu.edu.sa.
authors.forename: Nyla
authors.initials: N
authors.lastname: Nazir
authors.affiliation: Strategic Center for Diabetes Research, King Saud University, P.O. Box 18397, Riyadh, 11415, K.S.A, Saudi Arabia. ksiddiqui@ksu.edu.sa.
authors.forename: Khalid
authors.initials: K
authors.lastname: Siddiqui
authors.affiliation: Strategic Center for Diabetes Research, King Saud University, P.O. Box 18397, Riyadh, 11415, K.S.A, Saudi Arabia. sqassim@dsrcenter.org.
authors.forename: Sara
authors.initials: S
authors.lastname: Al-Qasim
authors.affiliation: Strategic Center for Diabetes Research, King Saud University, P.O. Box 18397, Riyadh, 11415, K.S.A, Saudi Arabia. dalnaqeb@dsrcenter.org.
authors.forename: Dhekra
authors.initials: D
authors.lastname: Al-Naqeb
mesh_terms: D018932:Chemokine CCL2 / Q000235:genetics*; D016206:Databases, Bibliographic; D003928:Diabetic Nephropathies / Q000235:genetics*; D053263:Gene Regulatory Networks; D056726:Genetic Association Studies / Q000379:methods; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A