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

Maria Tziastoudi; Ioannis Stefanidis; Elias Zintzaras

doi:10.1093/ckj/sfaa077

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

Clin Kidney J. 2020 Jul 12;13(5):768-781. doi: 10.1093/ckj/sfaa077. eCollection 2020 Oct.

Authors

Maria Tziastoudi¹, Ioannis Stefanidis², Elias Zintzaras^{1

3}

Affiliations

¹ Department of Biomathematics, University of Thessaly, School of Medicine, Larissa, Greece.
² Department of Nephrology, University of Thessaly, School of Medicine, Larissa, Greece.
³ The Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA.

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 (OR_G). 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.

Keywords: association; diabetic nephropathy; genetic; meta-analysis; polymorphisms; systematic review.

Publication types

Review