Genome-Wide Association Studies of Metabolites in Patients with CKD Identify Multiple Loci and Illuminate Tubular Transport Mechanisms

Abstract

The kidneys have a central role in the generation, turnover, transport, and excretion of metabolites, and these functions can be altered in CKD. Genetic studies of metabolite concentrations can identify proteins performing these functions. We conducted genome-wide association studies and aggregate rare variant tests of the concentrations of 139 serum metabolites and 41 urine metabolites, as well as their pairwise ratios and fractional excretions in up to 1168 patients with CKD. After correction for multiple testing, genome-wide significant associations were detected for 25 serum metabolites, two urine metabolites, and 259 serum and 14 urinary metabolite ratios. These included associations already known from population-based studies. Additional findings included an association for the uremic toxin putrescine and variants upstream of an enzyme catalyzing the oxidative deamination of polyamines (, -min=2.4×10), a relatively high carrier frequency (2%) for rare deleterious missense variants in that are collectively associated with serum ratios of medium-chain acylcarnitines (-burden=6.6×10), and associations of a common variant in with several ratios of lysine to neutral amino acids in urine, including the lysine/glutamine ratio (=2.2×10). The associations of this variant with ratios of lysine to specific neutral amino acids were much stronger than the association with lysine concentration alone. This finding is consistent with functioning as an exchanger of urinary cationic amino acids against specific intracellular neutral amino acids at the apical membrane of proximal tubular cells. Metabolomic indices of specific kidney functions in genetic studies may provide insight into human renal physiology.

Heritability and family-based GWAS analyses of the N-acyl ethanolamine and ceramide plasma lipidome

“…The novel association with CER[N(24)S(16)] we describe is consistent with the gene’s role in influencing CER[NS] production, through the formation of sphingosine (C18S) for CER[NS] biosynthesis, and the production of CER[NS] from ceramide 1-phosphate (C1P) (Figure 1). The other significant SNPs identified at the same locus which associated with this CER species have been previously identified in further GWAS studies of blood phospholipids 46 , red cell distribution width 47 , sphingomyelin 46 , and unknown blood metabolite X-10510 45 . All SNPs identified at this locus associated in the UKBiobank PheWAS assessment, and 2SMR analyses, with multiple blood cell counts and other hematological phenotypes (Table S8).…”

Big science and big data in nephrology

“…86,87 In addition, very recent integrative studies have linked metabolomic profiles to variants in genomic information, suggesting tight associations (m genome-wide association studies), for example, between lysine abundance in urine and variants in solute carrier transporters. 27 Urinary glycine and histidine concentrations, for instance, were also found to correspond to outcomes in the Framingham offspring cohort. 28 Whereas metabolites are commonly regarded as the output of protein activity, they can also modulate biological systems and thereby drive phenotypes.…”

Epidemiology research to foster improvement in chronic kidney disease care

“…99,100 Linking genetics to urine metabolomics can help elucidate tubular properties: for example, the strong association between SLC7A9 and the ratio of lysine to neutral amino acids in urine suggests genetic differences in amino acid exchange. 101 Pathway analyses have also been used to identify implicated metabolic pathways, such as phosphatidylethanolamines, a class of phospholipids, in proteinuria, 88 and in CKD years preceding ESKD. 102…”