Nidogen-1 Could Play a Role in Diabetic Kidney Disease Development: A Genome Wide Association Meta-analysis

Abstract Background:Diabetic kidney disease (DKD) affects about 40% of patients with diabetes. It is uncurable and usually lead to end-stage renal disease (ESRD). The pathogenesis of DKD is still not fully understood and the genetics of DKD have not yet been extensively studied.In this study we investigate the genetic basis of DKD in type 2 diabetes (T2D) to provide more insights into the pathogenesis of the disease.Results:Using the data provided by the UK Biobank (UKBB), we performed a DKD genome-wide association study (GWAS) in 13,123 individuals with T2D as well as two creatinine estimated glomerular filtration rate (eGFR) GWA studies; one in 28,136 individuals with T2D and the other in 339,080 non-diabetic individuals. We also conducted a DKD GWAS meta-analysis combining our results with those published by the SUMMIT consortium.We confirm two loci previously reported to be associated with chronic kidney disease (CKD) and eGFR in T2D. The UMOD-PDILT locus is associated with DKD (P = 1.08E-09) as well as creatinine eGFR in both people with T2D (P = 5.35E-15) and people without diabetes (P = 2.06E-72). The PRKAG2 locus is associated with creatinine eGFR in people with (P = 6.22E-10) and without (P = 2.61E-72) T2D. Our meta-analysis reveals a novel association between DKD and variant rs72763500 (chr1:236116561) which is a splicing quantitative trait locus (sQTL) for nidogen-1 (NID1) gene.Conclusion:Our data confirms two loci previously reported in association with CKD and creatinine eGFR in T2D. It also suggests that NID1, a major component of the renal tubular basement membrane, could play a role in DKD development in T2D. While our NID1 finding remains to be replicated, it is a step towards a more comprehensive understanding of DKD pathogenesis.