Metabolites as novel biomarkers for childhood obesity-related traits in Mexican-American children.

BACKGROUND/OBJECTIVES: Although newer approaches have identified several metabolites associated with obesity, there is paucity of such information in paediatric populations, especially among Mexican-Americans (MAs) who are at high risk of obesity. Therefore, we performed a global serum metabolite screening in MA children to identify biomarkers of childhood obesity. METHODS: We selected 15 normal-weight, 13 overweight and 14 obese MA children (6-17 years) and performed global serum metabolite screening using ultra-performance liquid chromatography/quadruple orthogonal acceleration time of flight tandem micro mass spectrometer. Metabolite values were analysed to assess mean differences among groups using one-way analysis of variance, to test for linear trend across groups and to examine Pearson's correlations between them and seven cardiometabolic traits (CMTs): body mass index, waist circumference, systolic blood pressure, diastolic blood pressure, homeostasis model of assessment-insulin resistance, triglycerides and high-density lipoprotein cholesterol. RESULTS: We identified 14 metabolites exhibiting differences between groups as well as linear trend across groups with nominal statistical significance. After adjustment for multiple testing, mean differences and linear trends across groups remained significant (P < 5.9 × 10(-5) ) for L-thyronine, bradykinin and naringenin. Of the examined metabolite-CMT trait pairs, all metabolites except for 2-methylbutyroylcarnitine were nominally associated with two or more CMTs, some exhibiting significance even after accounting for multiple testing (P < 3.6 × 10(-3) ). CONCLUSIONS: To our knowledge, this study - albeit pilot in nature - is the first study to identify these metabolites as novel biomarkers of childhood obesity and its correlates. These findings signify the need for future systematic investigations of metabolic pathways underlying childhood obesity.

Localization of a major susceptibility locus influencing preterm birth.

Preterm birth (PTB) is a complex trait, but little is known regarding its major genetic determinants. The objective of this study is to localize genes that influence susceptibility to PTB in Mexican Americans (MAs), a minority population in the USA, using predominantly microfilmed birth certificate-based data obtained from the San Antonio Family Birth Weight Study. Only 1302 singleton births from 288 families with information on PTB and significant covariates were considered for genetic analysis. PTB is defined as a childbirth that occurs at <37 completed weeks of gestation, and the prevalence of PTB in this sample was 6.4%. An ∼10 cM genetic map was used to conduct a genome-wide linkage analysis using the program SOLAR. The heritability of PTB was high (h(2) ± SE: 0.75 ± 0.20) and significant (P = 4.5 × 10(-5)), after adjusting for the significant effects of birthweight and birth order. We found significant evidence for linkage of PTB (LOD = 3.6; nominal P = 2.3 × 10(-5); empirical P = 1.0 × 10(-5)) on chromosome 18q between markers D18S1364 and D18S541. Several other chromosomal regions (2q, 9p, 16q and 20q) were also potentially linked with PTB. A strong positional candidate gene in the 18q linked region is SERPINB2 or PAI-2, a member of the plasminogen activator system that is associated with various reproductive processes. In conclusion, to our knowledge, perhaps for the first time in MAs or US populations, we have localized a major susceptibility locus for PTB on chromosome 18q21.33-q23.

Establishment of a gastric epithelial progenitor cell line from a transgenic mouse expressing the simian virus 40 large T antigen gene in the parietal cell lineage.

OBJECTIVE: In this study the gastric mucosa of transgenic mice expressing the simian virus 40 large T antigen gene in the parietal cell lineage is used to establish and characterize a new epithelial progenitor cell line. In these mice, proliferation and amplification of preparietal cells preclude their maturation into acid-secreting parietal cells leading to achlorohydria, hyperplasia, dysplasia and eventually gastric adenocarcinoma. MATERIALS AND METHODS: Enzymatically dispersed gastric epithelial cells were cultured, cloned and screened using immunohistochemical methods, for expression of a variety of biomarkers of differentiated pit, parietal, enteroendocrine and neck/zymogenic cells. RESULTS: A biomarker-deficient cell line whose ultrastructural features resembled those of mouse gastric epithelial progenitor cells was established. Treatment with either hydrocortisone or oestrogen significantly enhanced proliferation of these cells, whereas retinoic acid inhibited their growth. No change in differentiation was detected with any of these treatments; however, when these cells were injected subcutaneously into nude mice, they proliferated to form tumours and undergo partial differentiation towards parietal cell lineage. CONCLUSION: This mouse gastric epithelial progenitor cell line could be useful as an in vitro model to study growth properties, proliferation and differentiation of a subpopulation of gastric epithelial progenitor cells and also to study gastric carcinogenesis.

Variant screening of PRKAB2, a type 2 diabetes mellitus susceptibility candidate gene on 1q in Pima Indians.

The AMP-activated protein kinase (AMPK) is a key enzyme involved in the regulation of lipid and glucose metabolism. There are multiple isoforms of the three subunits of this enzymatic complex, each encoded by a different gene in humans. We have investigated the PRKAB2 gene encoding the beta2 subunit, which is located on chromosome 1q within a region linked with type 2 diabetes mellitus (T2DM) in the Pima Indians and four different Caucasian populations. The gene consists of eight exons spanning about 15 kb, and we detected nine variants in the introns and 3' UTR, including eight informative single nucleotide polymorphisms (SNPs) and one rare 4 bp insertion/deletion. In an analysis of representative markers in selected Pima Indians including 149 diabetic cases (onset age < 25 years) and 150 controls (at least 45 years old, with normal glucose tolerance), we found no evidence for association of this locus with T2DM. We conclude that variants in PRKAB2 are unlikely to contribute to the disease susceptibility in Pima Indians.

Analysis of MGEA5 on 10q24.1-q24.3 encoding the beta-O-linked N-acetylglucosaminidase as a candidate gene for type 2 diabetes mellitus in Pima Indians.

Several diseases including type 2 diabetes mellitus (T2DM) are associated with abnormal O-glycosylation of proteins. beta-O-linked N-acetylglucosaminidase (O-GlcNAcase) encoded by MGEA5 on 10g24.1-q24.3 removes N-acetylglucosamine (O-GlcNAc), and we investigated this locus in Pima Indians who have the world's highest prevalence of T2DM. We detected two variants but there was no association with parameters of insulin resistance or diabetes in approximately 1300 Pimas. We conclude that mutations in MGEA5 are unlikely to contribute to T2DM in this population.

Molecular fingerprinting of mupirocin-resistant methicillin-resistant Staphylococcus aureus from a burn unit.

OBJECTIVES: To characterize mupirocin-resistant methicillin-resistant Staphylococcus aureus (MRSA) isolated from patients in a burn unit by pulsed-field gel electrophoresis and plasmid contents. METHODS: A total of 53 methicillin-resistant S. aureus, consisting of 48 mupirocin-resistant and 5 mupirocin-susceptible MRSA were compared by plasmid content and pulsed-field gel electrophoresis of Sma I digested genomic DNA. RESULTS: Of the 48 mupirocin-resistant isolates, 39 expressed high-level, and 9 expressed low-level mupirocin resistance. Plasmids were detected in all of the 53 isolates; however, only the high-level mupirocin-resistant isolates contained a 38 kb-conjugative plasmid that encoded high-level mupirocin resistance. Pulsed-field gel electrophoresis divided the isolates into four patterns designated types I to IV. Forty-three isolates consisting of 34 high-level, 5 low-level mupirocin-resistant and 4 mupirocin-susceptible isolates defined the type-I pattern. Eight isolates, five high-level and three low-level mupirocin-resistant isolates had the type-II pulsed-field pattern. The type-III and type-IV pulsed-field patterns consisted of a single isolate each. The type-I and type-II pulsed-field patterns were related and only differed by four Sma I bands. CONCLUSIONS: Results of typing the mupirocin-resistant MRSA from the burn unit with pulsed-field gel electrophoresis indicated that closely related MRSA clones previously circulating in the unit had acquired a high-level mupirocin-resistant plasmid, and spread aided by mupirocin use.