ABSTRACT
Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals (P < 5 × 10-9). Notably, we identified and replicated a novel low frequency single nucleotide polymorphism (SNP) in MTMR3 that was common in individuals of African descent. Using a diverse study population, we further identified two novel secondary signals in known BMI loci and pinpointed two likely causal variants in the POC5 and DMD loci. Our work demonstrates the benefits of combining WGS and diverse cohorts in expanding current catalog of variants and genes confer risk for obesity, bringing us one step closer to personalized medicine.
ABSTRACT
BACKGROUND/OBJECTIVES: Obesity, defined as excessive fat accumulation that represents a health risk, is increasing in adults and children, reaching global epidemic proportions. Body mass index (BMI) correlates with body fat and future health risk, yet differs in prediction by fat distribution, across populations and by age. Nonetheless, few genetic studies of BMI have been conducted in ancestrally diverse populations. Gene expression association with BMI was assessed in the Multi-Ethnic Study of Atherosclerosis (MESA) in four self-identified race and ethnicity (SIRE) groups to identify genes associated with obesity. SUBJECTS/METHODS: RNA-sequencing was performed on 1096 MESA participants (37.8% white, 24.3% Hispanic, 28.4% African American, and 9.5% Chinese American) and linear models were used to assess the association of expression from each gene for its effect on BMI, adjusting for age, sex, sequencing center, study site, five expression and four genetic principal components in each self-identified race group. Sample-size-weighted meta-analysis was performed to identify genes with BMI-associated expression across ancestry groups. RESULTS: Within individual SIRE groups, there were zero to three genes whose expression is significantly (p < 1.97 × 10-6) associated with BMI. Across all groups, 45 genes were identified by meta-analysis whose expression was significantly associated with BMI, explaining 29.7% of BMI variation. The 45 genes are expressed in a variety of tissues and cell types and are enriched for obesity-related processes including erythrocyte function, oxygen binding and transport, and JAK-STAT signaling. CONCLUSIONS: We have identified genes whose expression is significantly associated with obesity in a multi-ethnic cohort. We have identified novel genes associated with BMI as well as confirmed previously identified genes from earlier genetic analyses. These novel genes and their biological pathways represent new targets for understanding the biology of obesity as well as new therapeutic intervention to reduce obesity and improve global public health.
Subject(s)
Body Mass Index , Gene Expression , Obesity , Adult , Child , Humans , Atherosclerosis , Obesity/epidemiology , Obesity/geneticsABSTRACT
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Subject(s)
Cardiovascular Diseases/blood , Cardiovascular Diseases/genetics , Lipopolysaccharide Receptors/blood , Lipopolysaccharide Receptors/genetics , Polymorphism, Single Nucleotide , Adult , Black or African American/genetics , Age Factors , Aged , Biomarkers/blood , Cardiovascular Diseases/ethnology , Cardiovascular Diseases/mortality , Cross-Sectional Studies , Female , Genetic Predisposition to Disease , Genome-Wide Association Study , Heart Disease Risk Factors , Humans , Incidence , Male , Middle Aged , Mississippi/epidemiology , Phenotype , Prognosis , Race Factors , Risk Assessment , Time FactorsABSTRACT
We report that fluoroquinolone-resistant Escherichia coli are found in feces of 8.8% of healthy women, with most bacteria belonging to pandemic multidrug-resistant ST131-H30R or ST1193 clonal groups. Moreover, these highly uropathogenic clonal groups demonstrate an especially prolonged gut persistence and high rate of bacteriuria without documented urinary tract infection.
Subject(s)
Bacteriuria , Escherichia coli Infections , Gastrointestinal Microbiome , Urinary Tract Infections , Uropathogenic Escherichia coli , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Bacteriuria/drug therapy , Bacteriuria/epidemiology , Drug Resistance, Multiple, Bacterial , Escherichia coli Infections/drug therapy , Escherichia coli Infections/epidemiology , Female , Fluoroquinolones/pharmacology , Humans , Pandemics , Urinary Tract Infections/drug therapy , Urinary Tract Infections/epidemiologyABSTRACT
We describe the rapid and ongoing emergence across multiple US cities of a new multidrug-resistant Escherichia coli clone-sequence type (ST) 1193-resistant to fluoroquinolones (100%), trimethoprim-sulfamethoxazole (55%), and tetracycline (53%). ST1193 is associated with younger adults (age <40 years) and currently comprises a quarter of fluoroquinolone-resistant clinical E. coli urine isolates.
