Exploring the Paradoxical Relationship of a Creb 3 Regulatory Factor Missense Variant With Body Mass Index and Diabetes Among Samoans: Protocol for the Soifua Manuia (Good Health) Observational Cohort Study

Abstract

Background The prevalence of obesity and diabetes in Samoa, like many other Pacific Island nations, has reached epidemic proportions. Although the etiology of these conditions can be largely attributed to the rapidly changing economic and nutritional environment, a recently identified genetic variant, rs373863828 (CREB 3 regulatory factor, CREBRF: c.1370G>A p.[R457Q]) is associated with increased odds of obesity, but paradoxically, decreased odds of diabetes. Objective The overarching goal of the Soifua Manuia (Good Health) study was to precisely characterize the association of the CREBRF variant with metabolic (body composition and glucose homeostasis) and behavioral traits (dietary intake, physical activity, sleep, and weight control behaviors) that influence energy homeostasis in 500 adults. Methods A cohort of adult Samoans who participated in a genome-wide association study of adiposity in Samoa in 2010 was followed up, based on the presence or absence of the CREBRF variant, between August 2017 and March 2019. Over a period of 7-10 days, each participant completed the main study protocol, which consisted of anthropometric measurements (weight, height, circumferences, and skinfolds), body composition assessment (bioelectrical impedance and dual-energy x-ray absorptiometry), point-of-care glycated hemoglobin measurement, a fasting blood draw and oral glucose tolerance test, urine collection, blood pressure measurement, hand grip strength measurement, objective physical activity and sleep apnea monitoring, and questionnaire measures (eg, health interview, cigarette and alcohol use, food frequency questionnaire, socioeconomic position, stress, social support, food and water insecurity, sleep, body image, and dietary preferences). In January 2019, a subsample of the study participants (n=118) completed a buttock fat biopsy procedure to collect subcutaneous adipose tissue samples. Results Enrollment of 519 participants was completed in March 2019. Data analyses are ongoing, with results expected in 2020 and 2021. Conclusions While the genetic variant rs373863828, in CREBRF, has the largest known effect size of any identified common obesity gene, very little is currently understood about the mechanisms by which it confers increased odds of obesity but paradoxically lowered odds of type 2 diabetes. The results of this study will provide insights into how the gene functions on a whole-body level, which could provide novel targets to prevent or treat obesity, diabetes, and associated metabolic disorders. This study represents the human arm of a comprehensive and integrated approach involving humans as well as preclinical models that will provide novel insights into metabolic disease. International Registered Report Identifier (IRRID) RR1-10.2196/17329

The association of CREBRF variant rs373863828 with body composition in adult Samoans

“…Participants with AA, AG, and GG genotypes were targeted in a 1:2:2 ratio. Protocols for the original GWAS in 2010 and the follow-up study, including genotyping methods, have been previously published [7,8].…”

“…Eligible participants were not pregnant, lactating, or attempting to control their weight through medication or surgery, were resident on the island of ‘Upolu and were part of a maximally unrelated sample [maximum kinship 6.01%] [8]. Willing participants ( n =519; aged 30.7-72.7 years) gave written informed consent.…”

CREBRF p.Arg457Gln Promotes Obesity and Improves Insulin Sensitivity by Promoting Preadipocyte Differentiation and Reducing Oxidative Metabolism in Gene-modified Pig Models

“…All the CREBRF p.Arg457Gln variant carriers, regardless of heterozygote or homozygote, male or female, displayed obviously increased body weight, abdominal circumference, and body length compared with the wild-type littermates. All these phenotypes were resulted from normal diet chow, similar to the human population with the same genotype 19,[21][22][23] . The model is different from obesity linked to diabetes models, such as over-expressing fat mass and obesity-associated (FTO) mice 44 , mice with genetic deletions of melanocortin 4 receptor(MC4R) 45 leptin-de cient mice 46 and zebra sh obesity models 47 , in which the obesity phenotype was primarily caused by increased appetite and food intake and decreased physical activity 48 .…”

“…Appropriate animal models are necessary to de ne the function of the CREBRF in relation to obesity and mechanisms for protection from T2DM. To date, most studies of CREBRF p.Arg457Gln are limited to the description of phenotypes among speci c human populations [18][19][20][21][22][23][24] . The CREBRF knock-out mice has been used to examine anxiety-like behavior and circulating glucocorticoids in response to various acute stress conditions 25,26 .…”

C‐reactive protein in adult Samoans: Population variation and physiological correlates

“…Here we present a secondary, cross-sectional analysis of correlates of CRP in a sample of adult Samoans (ages 35-55 years). Participants were a subsample (n = 108, 50.9% female) of adults who participated in the Soifua Manuia ("Good Health") study of adiposity between 2017 and 2019 (Hawley et al, 2020). The Soifua Manuia study followed up with n = 519 individuals who had participated in a 2010 genome-wide association study that identified a missense variant in the CREBRF gene associated with increased BMI (Minster et al, 2016).…”