Matthew B. McQueen - US grants

DESCRIPTION (provided by applicant): Evidence from biometric and molecular studies indicates that genetic factors significantly influence body mass among humans. This has led to recent efforts to identify single nucleotide polymorphisms (SNPs) across to the entire human genome that are associated with adult and adolescent weight. However, all existing genome wide association (GWA) studies of body mass and obesity have focused on main genetic effects rather than interaction effects between genetic and environmental factors. This leads to gene-environment interaction (GxE) studies that focus on environmental factors that moderate genetic main effects. In the event that there are only genetic effects within particular environments (e.g., no main genetic effects), then current GWA models will overlook important genetic influences. Because body mass is strongly influenced by social environmental factors and because genetic associations for body mass are contingent upon social- environmental influences, environmental risk (and protective) factors must be included in the conceptual understandings and methodological approaches to GWA. While GxE studies involving a single genetic variant are increasingly common, no existing work has specifically focused on genome-wide approaches to GxE. Our approach is a fundamentally new way of examining genetic influences on body mass that extends established GWA methods and draws upon established GxE theory. PUBLIC HEALTH RELEVANCE: This project will provide a comprehensive evaluation of the complex gene-by-environment etiology underlying physical body size on the genome-wide scale. Identification of important gene-by-environment interactions contributing to body mass will reveal important biological mechanisms underlying obesity, detect potential targets for pharmaceutical development and identify populations "at risk".

ABSTRACT Age-related immune dysregulation and increases in inflammation, termed inflammaging, have been consistently implicated in most common age-related diseases, but the precise etiology of inter-individual differences in inflammaging are unknown. Changes in immunity and inflammation occur throughout the life course, but research on these processes among non-elderly populations has been limited. This is important because identifying sources of biological aging and inflammation before individuals reach older age may help identify points for intervention. The composition of the gut microbiota has been shown in animal models to have profound influence over, and interactions with, the immune system. Findings from germ-free mice suggest that commensal gut microbes are a key cause of inflammaging, but this hypothesis has not been well- explored in humans. There are currently very few data examining how the microbiome relates to the fundamental aspects of aging biology, specifically inflammatory phenotypes and genomic markers of biological age. We propose to fill gaps in current microbiome research on aging, through the collection and analysis of oral and gut microbiome data in The National Longitudinal Study of Adolescent to Adult Health (Add Health), a nationally representative longitudinal cohort of adults with extensive social environment data and existing or ongoing analyses of genomic and phenotypic markers of inflammation and aging. The specific aims include the: 1) Collection of tongue and stool specimens with which to characterize the oral and gut microbiome in a nationally-representative sample (N ~10,155) of Add Health participants (mean age ~40); 2) Testing the association between the microbiome and biomarkers of aging and inflammation, and the creation of a novel ?microbiome age clock?; 3) Examination of the relationships between life course exposures and microbiome species related to biomarkers of aging and inflammation as an adult; 4) Documentation and dissemination of data generated from this project. This proposal represents the first study to assess how the oral and gut microbiome are associated with biomarkers of DNA methylation aging and inflammation in a large US representative sample of midlife adults. Our study will significantly advance our understanding of the life course exposures from gestation to adulthood that shape microbiome markers of inflammaging and DNA methylation aging. This is crucial because identifying microbiome markers of biological aging in adulthood will allow us to better identify signs of early aging via the microbiome.