Metabolomic Changes in Serum of Children with Different Clinical Diagnoses of Malnutrition.

BACKGROUND: Mortality in children with severe acute malnutrition (SAM) remains high despite standardized rehabilitation protocols. Two forms of SAM are classically distinguished: kwashiorkor and marasmus. Children with kwashiorkor have nutritional edema and metabolic disturbances, including hypoalbuminemia and hepatic steatosis, whereas marasmus is characterized by severe wasting. The metabolic changes underlying these phenotypes have been poorly characterized, and whether homeostasis is achieved during hospital stay is unclear. OBJECTIVES: We aimed to characterize metabolic differences between children with marasmus and kwashiorkor at hospital admission and after clinical stabilization and to compare them with stunted and nonstunted community controls. METHODS: We studied children aged 9-59 mo from Malawi who were hospitalized with SAM (n = 40; 21 with kwashiorkor and 19 with marasmus) or living in the community (n = 157; 78 stunted and 79 nonstunted). Serum from patients with SAM was obtained at hospital admission and 3 d after nutritional stabilization and from community controls. With the use of targeted metabolomics, 141 metabolites, including amino acids, biogenic amines, acylcarnitines, sphingomyelins, and phosphatidylcholines, were measured. RESULTS: At admission, most metabolites (128 of 141; 91%) were lower in children with kwashiorkor than in those with marasmus, with significant differences in several amino acids and biogenic amines, including those of the kynurenine-tryptophan pathway. Several phosphatidylcholines and some acylcarnitines also differed. Patients with SAM had profiles that were profoundly different from those of stunted and nonstunted controls, even after clinical stabilization. Amino acids and biogenic amines generally improved with nutritional rehabilitation, but most sphingomyelins and phosphatidylcholines did not. CONCLUSIONS: Children with kwashiorkor were metabolically distinct from those with marasmus, and were more prone to severe metabolic disruptions. Children with SAM showed metabolic profiles that were profoundly different from stunted and nonstunted controls, even after clinical stabilization. Therefore, metabolic recovery in children with SAM likely extends beyond discharge, which may explain the poor long-term outcomes in these children. This trial was registered at isrctn.org as ISRCTN13916953.

A Candidate-Gene Approach Identifies Novel Associations Between Common Variants in/Near Syndromic Obesity Genes and BMI in Pediatric and Adult European Populations.

We hypothesized that monogenic syndromic obesity genes are also involved in the polygenic variation of BMI. Single-marker, tag single nucleotide polymorphism (tagSNP) and gene-based analysis were performed on common variants near 54 syndromic obesity genes. We used publicly available data from meta-analyses of European BMI genome-wide association studies conducted by the Genetic Investigation of ANthropometric Traits (GIANT) Consortium and the UK Biobank (UKB) (N = 681,275 adults). A total of 33 loci were identified, of which 19 of 33 (57.6%) were located at SNPs previously identified by the GIANT Consortium and UKB meta-analysis, 11 of 33 (33.3%) were located at novel SNPs, and 3 of 33 (9.1%) were novel genes identified with gene-based analysis. Both single-marker and tagSNP analyses mapped the previously identified 19 SNPs by the GIANT Consortium and UKB meta-analysis. Gene-based analysis confirmed 15 of 19 (78.9%) of the novel SNPs' associated genes. Of the 11 novel loci, 8 were identified with single-marker analysis and the remaining 3 were identified with tagSNP analysis. Gene-based analysis confirmed 4 of 11 (36.3%) of these loci. Meta-analysis with the Early Growth Genetics (EGG) Consortium (N = 35,668 children) was conducted post hoc for top SNPs, confirming 17 of 33 (51.5%) loci, of which 5 were novel. This study supports evidence for a continuum between rare monogenic syndromic and common polygenic forms of obesity.

Comprehensive identification of pleiotropic loci for body fat distribution using the NHGRI-EBI Catalog of published genome-wide association studies.

We conducted a hypothesis-free cross-trait analysis for waist-to-hip ratio adjusted for body mass index (WHRadjBMI ) loci derived through genome-wide association studies (GWAS). Summary statistics from published GWAS were used to capture all WHRadjBMI single-nucleotide polymorphisms (SNPs), and their proxy SNPs were identified. These SNPs were used to extract cross-trait associations between WHRadjBMI SNPs and other traits through the NHGRI-EBI GWAS Catalog. Pathway analysis was conducted for pleiotropic WHRadjBMI SNPs. We found 160 WHRadjBMI SNPs and 3675 proxy SNPs. Cross-trait analysis identified 239 associations, of which 100 were for obesity traits. The remaining 139 associations were filtered down to 101 unique linkage disequilibrium block associations, which were grouped into 13 categories: lipids, red blood cell traits, white blood cell counts, inflammatory markers and autoimmune diseases, type 2 diabetes-related traits, adiponectin, cancers, blood pressure, height, neuropsychiatric disorders, electrocardiography changes, urea measurement, and others. The highest number of cross-trait associations were found for triglycerides (n = 10), high-density lipoprotein cholesterol (n = 9), and reticulocyte counts (n = 8). Pathway analysis for WHRadjBMI pleiotropic SNPs found immune function pathways as the top canonical pathways. Results from our original methodology indicate a novel genetic association between WHRadjBMI and reticulocyte counts and highlight the pleiotropy between abdominal obesity, immune pathways, and other traits.