Identifying Genetic Variants and Metabolites Associated with Rapid Estimated Glomerular Filtration Rate Decline in Korea Based on Genome–Metabolomic Integrative Analysis

Abstract

Identifying the predisposing factors to chronic or end-stage kidney disease is essential to preventing or slowing kidney function decline. Therefore, here, we investigated the genetic variants related to a rapid decline in the estimated glomerular filtration rate (eGFR) (i.e., a loss of >5 mL/min/1.73 m2 per year) and verified the relationships between variant-related diseases and metabolic pathway signaling in patients with chronic kidney disease. We conducted a genome-wide association study that included participants with diabetes, hypertension, and rapid eGFR decline from two Korean data sources (N = 115 and 69 for the discovery and the validation cohorts, respectively). We identified a novel susceptibility locus: 4q32.3 (rs10009742 in the MARCHF1 gene, beta = −3.540, P = 4.11 × 10−8). Fine-mapping revealed 19 credible, causal single-nucleotide polymorphisms, including rs10009742. The pimelylcarnitine and octadecenoyl carnitine serum concentrations were associated with rs10009742 (beta = 0.030, P = 7.10 × 10−5, false discovery rate (FDR) = 0.01; beta = 0.167, P = 8.11 × 10−4, FDR = 0.08). Our results suggest that MARCHF1 is associated with a rapid eGFR decline in patients with hypertension and diabetes. Furthermore, MARCHF1 affects the pimelylcarnitine metabolite concentration, which may mediate chronic kidney disease progression by inducing oxidative stress in the endoplasmic reticulum.

The genetic communication and interaction between chronic kidney diseases and frailty

“…25 Lee et al reported that MARCHF1, a regulator of lipid metabolism and glucose tolerance, could potentially contribute to the progression of CKD by causing oxidative stress in the proximal tubular endoplasmic reticulum. 26,27 TA B L E 1 Genome-Wide Association Studies in kidney function.…”

“…25 Lee et al reported that MARCHF1, a regulator of lipid metabolism and glucose tolerance, could potentially contribute to the progression of CKD by causing oxidative stress in the proximal tubular endoplasmic reticulum. 26,27 Hereditary CKD refers to CKD that is caused by genetic factors. With the continuous advancement of genetic sequencing, candidate genes for hereditary CKD have been steadily discovered, thus expanding the scope of this disease.…”