In this competitive renewal we focus on characterizing a novel missense variant that was identified by genome- wide association analysis (GWAS) of obesity-related traits in Samoans during the previous funding period. This missense variant is highly associated with body mass index (BMI) with an effect size greater than any other known common obesity risk variant. The gene harboring this missense variant encodes a putative transcription factor (TF) that has recently been implicated in energy metabolism in Drosophila but remains poorly characterized, particularly in higher organisms. Preliminary data presented in this application indicate that overexpression of both the wild-type human gene and its missense variant in 3T3L1 adipocytes enhances adipogenesis, promotes lipid storage, and improves cell survival. In addition, overexpression of the missense variant promotes even greater lipid storage and reduces energy substrate oxidation, suggesting that it is a ?thrifty? variant. Given the enormous contribution of obesity to disease, additional studies are urgently needed to understand the mechanisms by which this missense variant contributes to obesity in humans. The Central Aim of this proposal is to determine how the TF gene and its missense variant contribute to energy homeostasis and to identify the transcriptional pathways mediating these effects. We will achieve this goal using integrated studies in cells, mice, and humans to understand the molecular, physiological, and clinical relevance of the missense variant. The following Specific Aims will be pursued:
Aim 1 will identify and characterize the gene networks mediating the effects of the TF gene and its missense variant on energy homeostasis and energy substrate metabolism in cultured cells, a range of metabolically-relevant tissues from mice, and adipose tissue from 123 Samoans;
Aim 2 will characterize the impact of the missense variant on whole body and tissue-specific energy homeostasis and energy substrate metabolism using variant-specific knockin mice;
Aim 3 will more precisely characterize the impact of the missense variant on metabolic and behavioral traits that impact energy homeostasis in a subset of 500 Samoans GWAS participants who will be selected based on their genotype. These deeper phenotypes will be measured with new fieldwork in Samoa by re-contacting participants from the original GWAS study, during which metabolic and nutritional conditions/exposures analogous to those used in Aims 1 and 2 will be tested;
Aim 4 will more fully characterize the missense variant using comprehensive statistical approaches including testing for selective signatures, testing for pleiotropy via multivariate analyses, performing pathway analyses, testing for missense variant x environment interactions with a focus on diet and physical activity, testing for TF gene x gene interactions focusing on genes identified in Aims 1 and 2, and testing for association with newly gathered phenotypes from Aim 3. Successful completion of these aims will promote the understanding of obesity and its downstream health outcomes as well as identify novel targets for pharmacological interventions.

Public Health Relevance

By studying, in cell models, mice, and humans, the effects of a genetic variant that makes cells accumulate fat while using less energy, this project will help us understand the basic biological underpinnings of obesity and related health outcomes. The proposed research is relevant to public health because it will characterize novel mechanisms contributing to obesity, a highly prevalent disorder with high morbidity/mortality. This research is relevant to the NIH mission of advancing the understanding, prevention, and treatment of obesity and heart diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL093093-06
Application #
9175412
Study Section
Kidney, Nutrition, Obesity and Diabetes (KNOD)
Program Officer
Papanicolaou, George
Project Start
2009-09-01
Project End
2020-04-30
Budget Start
2016-07-01
Budget End
2017-04-30
Support Year
6
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Brown University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
Maredia, H; Hawley, N L; Lambert-Messerlian, G et al. (2018) Reproductive health, obesity, and cardiometabolic risk factors among Samoan women. Am J Hum Biol 30:e23106
Linhart, Christine; Naseri, Take; Lin, Sophia et al. (2018) Continued increases in blood pressure over two decades in Samoa (1991-2013); around one-third of the increase explained by rising obesity levels. BMC Public Health 18:1122
Wang, Dongqing; Hawley, Nicola L; Thompson, Avery A et al. (2017) Dietary Patterns Are Associated with Metabolic Outcomes among Adult Samoans in a Cross-Sectional Study. J Nutr 147:628-635
Linhart, Christine; Naseri, Take; Lin, Sophia et al. (2017) Tobacco smoking trends in Samoa over four decades: can continued globalization rectify that which it has wrought? Global Health 13:31
Lin, Sophia; Naseri, Take; Linhart, Christine et al. (2017) Diabetes incidence and projections from prevalence surveys in Samoa over 1978-2013. Int J Public Health 62:687-694
NCD Risk Factor Collaboration (NCD-RisC) (2017) Worldwide trends in blood pressure from 1975 to 2015: a pooled analysis of 1479 population-based measurement studies with 19ยท1 million participants. Lancet 389:37-55
Lin, S; Naseri, T; Linhart, C et al. (2017) Trends in diabetes and obesity in Samoa over 35 years, 1978-2013. Diabet Med 34:654-661
Falabella, Micol; Sun, Linqing; Barr, Justin et al. (2017) Single-Step qPCR and dPCR Detection of Diverse CRISPR-Cas9 Gene Editing Events In Vivo. G3 (Bethesda) 7:3533-3542
Maredia, Hasina; Lambert-Messerlian, Geralyn M; Palomaki, Glenn E et al. (2016) Cut-off levels for hyperandrogenemia among Samoan women: An improved methodology for deriving normative data in an obese population. Clin Biochem 49:782-6
Minster, Ryan L; Hawley, Nicola L; Su, Chi-Ting et al. (2016) A thrifty variant in CREBRF strongly influences body mass index in Samoans. Nat Genet 48:1049-1054

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