The genetic map of diabetic nephropathy: evidence from a systematic review and meta-analysis of genetic association studies

Abstract

Despite the extensive efforts of scientists, the genetic background of diabetic nephropathy (DN) has not yet been clarified. To elucidate the genetic variants that predispose to the development of DN, we conducted a systematic review and meta-analysis of all available genetic association studies (GAS) of DN. We searched in the Human Genome Epidemiology Navigator (HuGE Navigator) and PubMed for available GAS of DN. The threshold for meta-analysis was three studies per genetic variant. The association between genotype distribution and DN was examined using the generalized linear odds ratio (ORG). For variants with available allele frequencies, the examined model was the allele contrast. The pooled OR was estimated using the DerSimonian and Laird random effects model. The publication bias was assessed with Egger’s test. We performed pathway analysis of significant genes with DAVID 6.7. Genetic data of 606 variants located in 228 genes were retrieved from 360 GASs and were synthesized with meta-analytic methods. ACACB, angiotensin I-converting enzyme (ACE), ADIPOQ, AGT, AGTR1, AKR1B1, APOC1, APOE, ATP1B2, ATP2A3, CARS, CCR5, CGNL1, Carnosine dipeptidase 1 (CNDP1), CYGB-PRCD, EDN1, Engulfment and cell motility 1 (ELMO1), ENPP1, EPO, FLT4, FTO, GLO1, HMGA2, IGF2/INS/TH cluster, interleukin 1B (IL1B), IL8, IL10, KCNQ1, KNG, LOC101927627, Methylenetetrahydrofolate reductase, nitric oxide synthase 3 (NOS3), SET domain containing seven, histone lysine methyltransferase (SETD7), Sirtuin 1 (SIRT1), SLC2A1, SLC2A2, SLC12A3, SLC19A3, TCF7L2, TGFB1, TIMP1, TTC39C, UNC13B, VEGFA, WTAPP1, WWC1 as well as XYLT1 and three intergenic polymorphisms showed significant association with DN. Pathway analysis revealed the overrepresentation of six signalling pathways. The significant findings provide further evidence for genetic factors implication in DN offering new perspectives in discovery of new therapies.

Advances in understanding the innate immune‐associated diabetic kidney disease

“…80 The same variant of IL-4 and IL-6 genes were also associated with kidney function in the Japanese population. 81 In addition, GWAS variants in some other inflammation regulatory genes such as engulfment and cell motility protein 1 (ELMO1), TGF-β, TNF-α, CCR5, IL-1β, IL-8, IL-10, IL-18, MMP9, and TNF receptor-associated factor 6 are linked with the pathogenesis of DKD, 82,83 and some of these variants differ across populations. For instance, ELMO1-rs741301, ELMO1-rs10951509, and CCR5-rs1799987 in Chinese, ELMO1-intron 18+9170 in Japanese, TGF-β-rs1800470 in Chinese, Egyptians, and Mexicans, TGF-β-rs1800471 in Mexicans, and IL-8-rs4073 in Indians.…”

Oxidative Stress Genes in Diabetes Mellitus Type 2: Association with Diabetic Kidney Disease

“…A number of SNPs and their corresponding genes have been associated with DKD in several populations and studies. The engulfment and cell motility 1 (ELMO1) gene has shown an association with DKD in a Japanese population [ 29 ], a finding verified in a review and meta-analysis including both DM1 and DM2 populations of different origin [ 30 ]. The sterol regulatory element-binding protein-1 gene (SREBPF-1) has been also found to contribute to DM2 and DKD in a French, obese population suffering from DM2 as well as in mice [ 31 , 32 ].…”

“…Polymorphisms of the Transcription Factor 7-Like 2 (TCF7L2) gene have been associated with DM2 incidence in European and African-American populations, suffering from micro and macrovascular complications of DM2 including DKD [ 33 , 34 ]. The C677T variant of the methylenetetrahydrofolate reductase (MTHFR) gene on the metabolic pathway of homocysteine has been associated with DKD presentation and progression in DM2 populations of south Indian [ 35 ] and Tunisian origin [ 36 ] and in a meta-analysis including several studies [ 30 ]. Polymorphisms in the nonmuscle myosin IIA gene (MYH9) have been associated with ESKD susceptibility in a European American population with DM2 [ 37 ].…”

The Aggressive Diabetic Kidney Disease in Youth-Onset Type 2 Diabetes: Pathogenetic Mechanisms and Potential Therapies

“…The main factors triggering the dysregulation of DKD pathways comprehend persistent hyperglycemia, obesity-related factors, β-cell failure, and insulin resistance. Both murine and human studies demonstrated that the increased cellular sugar concentration is the primary trigger leading to ESRD progression [ 108 ].…”