Association of Variants at UMOD with Chronic Kidney Disease and Kidney Stones—Role of Age and Comorbid Diseases

Chronic kidney disease (CKD) is a worldwide public health problem that is associated with substantial morbidity and mortality. To search for sequence variants that associate with CKD, we conducted a genome-wide association study (GWAS) that included a total of 3,203 Icelandic cases and 38,782 controls. We observed an association between CKD and a variant with 80% population frequency, rs4293393-T, positioned next to the UMOD gene (GeneID: 7369) on chromosome 16p12 (OR = 1.25, P = 4.1×10⁻¹⁰). This gene encodes uromodulin (Tamm-Horsfall protein), the most abundant protein in mammalian urine. The variant also associates significantly with serum creatinine concentration (SCr) in Icelandic subjects (N = 24,635, P = 1.3×10⁻²³) but not in a smaller set of healthy Dutch controls (N = 1,819, P = 0.39). Our findings validate the association between the UMOD variant and both CKD and SCr recently discovered in a large GWAS. In the Icelandic dataset, we demonstrate that the effect on SCr increases substantially with both age (P = 3.0×10⁻¹⁷) and number of comorbid diseases (P = 0.008). The association with CKD is also stronger in the older age groups. These results suggest that the UMOD variant may influence the adaptation of the kidney to age-related risk factors of kidney disease such as hypertension and diabetes. The variant also associates with serum urea (P = 1.0×10⁻⁶), uric acid (P = 0.0064), and suggestively with gout. In contrast to CKD, the UMOD variant confers protection against kidney stones when studied in 3,617 Icelandic and Dutch kidney stone cases and 43,201 controls (OR = 0.88, P = 5.7×10⁻⁵).     

A compendium of inborn errors of metabolism mapped onto the human metabolic network

Inborn errors of metabolism (IEMs) are hereditary metabolic defects, which are encountered in almost all major metabolic pathways occurring in man. Many IEMs are screened for in neonates through metabolomic analysis of dried blood spot samples. To enable the mapping of these metabolomic data onto the published human metabolic reconstruction, we added missing reactions and pathways involved in acylcarnitine (AC) and fatty acid oxidation (FAO) metabolism. Using literary data, we reconstructed an AC/FAO module consisting of 352 reactions and 139 metabolites. When this module was combined with the human metabolic reconstruction, the synthesis of 39 acylcarnitines and 22 amino acids, which are routinely measured, was captured and 235 distinct IEMs could be mapped. We collected phenotypic and clinical features for each IEM enabling comprehensive classification. We found that carbohydrate, amino acid, and lipid metabolism were most affected by the IEMs, while the brain was the most commonly affected organ. Furthermore, we analyzed the IEMs in the context of metabolic network topology to gain insight into common features between metabolically connected IEMs. While many known examples were identified, we discovered some surprising IEM pairs that shared reactions as well as clinical features but not necessarily causal genes. Moreover, we could also re-confirm that acetyl-CoA acts as a central metabolite. This network based analysis leads to further insight of hot spots in human metabolism with respect to IEMs. The presented comprehensive knowledge base of IEMs will provide a valuable tool in studying metabolic changes involved in inherited metabolic diseases.     

Formation of 9-hydroxyoctadecadienoic acid from linoleic acid in endothelial cells

Human umbilical vein endothelial cells convert linoleic acid to two monohydroxyoctadecadienoic (HODE) acids, 9- and 13-HODE. More 9-HODE than 13-HODE is formed under most conditions. The production of these metabolites is reduced substantially by acetylsalicylic acid, ibuprofen, or arachidonic acid, suggesting that cyclooxygenase may be involved in endothelial HODE synthesis. Incubations lasting up to 4 h indicate that the endothelial cells can convert [U-14C] linoleic acid into at least four additional products, some of which may be derived from the HODE that is formed initially. Radioactive 9- and 13-HODE are produced when the endothelial cells are labeled with linoleic acid and then exposed to thrombin, suggesting that these metabolites also may be formed when the endothelium is activated. If endothelial monolayers grown on micropore filters are incubated with linoleic acid, a substantial amount of the HODE formed accumulates in the basolateral fluid. This suggests that HODE may have extracellular effects, especially within the vascular wall. Furthermore, when 9- or 13-HODE are added, endothelial cultures produce less prostaglandin I2 and convert less 12-hydroxyeicosatetraenoic acid to its main metabolite, 8-hydroxyhexadecatrienoic acid. Therefore, in addition to extracellular actions, HODE also may have functional effects within the endothelium.