A missense variant in CREBRF is associated with taller stature in Samoans

Abstract

ObjectivesStudies have demonstrated that rs373863828, a missense mutation in CREBRF, is associated with a number of anthropometric traits including body mass index (BMI), obesity, percent body fat, hip circumference, and abdominal circumference. Given the biological relationship between height and adiposity, we hypothesized that the effect of this variant on BMI might be due in part to a previously untested association of this variant with height.MethodsWe tested the hypothesis that minor allele of rs373863828 is associated with height in a Samoan population in two adult cohorts and in a separate cohort of children (age 5 - 18 years old) using linear mixed modeling.ResultsWe found evidence of a strong relationship between rs373863828 and greater mean height in Samoan adults (0.77 cm greater average height for each copy of the minor allele) with the same direction of effect in Samoan children.ConclusionsThese results suggest that the missense variant rs373863828 in CREBRF, first identified through an association with larger BMI, may be related to an underlying biological mechanism affecting overall body size including stature.

The minor allele of the CREBRF rs373863828 p.R457Q coding variant is associated with reduced levels of myostatin in males: Implications for body composition

“…Given that it is known there is sexual dimorphism in the regulation of myostatin [25,31,46] it is possible that different effects will be observed in women. Other sexually dimorphic effects of rs373863828 have been observed, for example the male-specific effects observed on height [17,47] and differences in the pattern of body composition between males and females [15]. Further studies will be required to resolve these issues.…”

Population specific reference panels are crucial for the genetic analyses of Native Hawai’ians: an example of theCREBRFlocus

“…The CREBRF variant has been reported to have a large effect on body mass index (BMI) in several populations from the Pacific Islands, and significantly associated with height and other adiposity traits in Samoans 11,40 . To explore its impact in Native Hawai'ians, where the derived allele is present at a relatively lower frequency compared to the Samoan discovery cohorts (26%), we conducted linear mixed association tests for the variant among genotyped individuals who also had available a collection of quantitative anthropometric, metabolic, and lipid phenotypes (Table S2 and Table S3).…”

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 .…”