A missense variant in CREBRF, rs373863828, is associated with fat-free mass, not fat mass in Samoan infants

Arslanian, Kendall; Fidow, Ulai T.; Atanoa, Theresa; Unasa-Apelu, F.; Naseri, Take; Wetzel, Abigail; Pomer, Alysa; Duckham, Rachel L.; McGarvey, Stephen T.; Strayer, Joshua A; Kershaw, Erin E.; Weeks, Daniel E.; Hawley, Nicola L.

doi:10.1038/s41366-020-00659-4

Cited by 22 publications

(28 citation statements)

References 28 publications

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“…The findings do not support the hypothesis that the inverse association between the A allele and type 2 diabetes is mediated by more metabolically favorable fat distribution. They are, however, consistent with our recent work in infants where we observed greater lean mass at four months of age [15] among those with the A allele. While it is not possible to obtain the same measures of fat distribution measures in infants, we saw no effect on total or percent fat mass.…”

Section: Discussionsupporting

confidence: 93%

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

Hawley

Duckham

et al. 2021

Preprint

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Objective: The minor allele of rs373863828, a missense variant in CREBRF, is associated with higher BMI but lower odds of type 2 diabetes in Pacific Islanders. Methods: To test if this protective effect operates through metabolically favorable body fat distribution, we examined the association of the minor A allele with body composition, measured using dual-energy x-ray absorptiometry (DXA), in a cross-sectional study of n=421 Samoan adults. Results: We replicated our earlier finding that this allele was associated with higher weight and BMI, although it was statistically significant only in women. There was no significant association of genotype with percent body fat, visceral adiposity or fat distribution, although in women, the A allele was associated with greater total fat mass (p=0.02), android (p=0.009) and trunk fat (p=0.01). In both sexes, age- and height-adjusted average lean mass was significantly greater per copy of the A allele: 2.16 kg/copy in women and 1.73 kg/copy in men. Conclusions: These data do not support a primary role of fat distribution in mediating the association between rs373863828 genotype and type 2 diabetes risk. We suggest an alternative hypothesis: those with the A allele may more efficiently regulate blood glucose because of their greater absolute lean mass.

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Section: Discussionsupporting

confidence: 93%

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

Hawley

Duckham

et al. 2021

Preprint

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“…Consistent with this, the A allele of rs373863828 associates with greater lean mass in infants [20]. Both higher muscle mass and metabolically-favourable adipose tissue distribution could improve insulin sensitivity to protect from diabetes.…”

Section: Introductionsupporting

confidence: 53%

“…An alternative hypothesis for the inverse risk relationship between T2D and BMI is that higher relative muscle mass may partially account for the increased BMI, increasing the ability to dispose of glucose. Consistent with this, the A allele of rs373863828 associates with greater lean mass in infants [20]. Both higher muscle mass and metabolically-favourable adipose tissue distribution could improve insulin sensitivity to protect from diabetes.…”

Section: Introductionmentioning

confidence: 77%

“…Recently, the A allele of rs373863828 has been shown to associate with increased growth of lean and bone mass in the first 4-months of life in Samoan infants [20]. Whether β-cell mass follows this same trajectory has yet to be determined, but it is interesting to speculate that the A allele promotes greater β-cell mass by adulthood, and thus a greater capacity to produce insulin to control blood glucose concentration when faced with environmental factors that would otherwise promote β-cell loss and T2D.…”

Section: Discussionmentioning

confidence: 99%

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The CREBRF diabetes-protective rs373863828-A allele is associated with enhanced early insulin release in men of Māori and Pacific ancestry

Burden

Adams

Kulatea

et al. 2021

Preprint

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Aim: The minor A allele of rs373863828 (CREBRF p.Arg457Gln) is associated with increased body mass index (BMI), but reduced risk of type 2 and gestational diabetes in Polynesian (Pacific peoples and Aotearoa New Zealand Māori) populations. This study investigates the effect of the A allele on insulin release and sensitivity in overweight/obese men without diabetes. Methods: A mixed meal tolerance test was completed by 172 men (56 with the A allele) of Māori or Pacific ancestry, and 44 (24 with the A allele) had a frequently sampled intravenous glucose tolerance test and hyperinsulinemic-euglycemic clamp. Mixed linear models with covariates age, ancestry and BMI were used to analyse the association between the A allele of rs373863828 and markers of insulin release and blood glucose regulation. Results: The A allele of rs373863828 is associated with a greater increase in plasma insulin 30 min following a meal challenge without affecting the elevation in plasma glucose or incretins GLP-1 or GIP. Consistent with this point, following an intravenous infusion of a glucose bolus, participants with an A allele had higher early (p<0.05 at 2 and 4 min) plasma insulin and C-peptide concentrations for a similar elevation in blood glucose as those homozygous for the major (G) allele. Despite increased plasma insulin, rs373863828 genotype was not associated with a significant difference (p>0.05) in insulin sensitivity index or glucose disposal during hyperinsulinemic-euglycemic clamp. Conclusion/interpretation: rs373863828-A allele associates with increased glucose-stimulated insulin release without affecting insulin sensitivity, suggesting that CREBRF p.Arg457Gln may increase maximal ability for β-cells to release insulin to reduce the risk of type 2 diabetes.

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“…There is evidence that it has multiple, tissue-specific function. The rs373863828 minor allele is associated with greater bone and lean mass in Samoan infants at four months old, but it is not associated with BMI [36], suggesting that body composition may be involved in the association between rs373863828, type 2 diabetes, and BMI. Another function is indicated by the analog of CREBRF in Drosophila which is involved in energy homeostasis [37], and along with one of its binding partners, CREBL2, it functions as a metabolic regulator linking nutrient sensor mTORC1 to cellular metabolic response [38].…”

Section: Discussionmentioning

confidence: 99%

CREBRF missense variant rs373863828 has both direct and indirect effects on type 2 diabetes and fasting glucose in Polynesians living in Samoa and Aotearoa New Zealand

Russell

Carlson

Krishnan

et al. 2021

Preprint

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Objective The minor allele of rs373863828 in CREBRF is associated with higher BMI, lower fasting glucose, and lower odds of type 2 diabetes. We examined the associations between BMI and rs373863828 on type 2 diabetes and fasting glucose with a large sample of adult Polynesians from Samoa, American Samoa and Aotearoa New Zealand and estimated direct and indirect (via BMI) effects of rs373863828 on type 2 diabetes and fasting glucose. Research Design and Methods We regressed type 2 diabetes and fasting glucose on BMI and rs373863828 stratified by obesity, regressed type 2 diabetes and fasting glucose on BMI stratified by rs373863828 genotype, and assessed the effects of rs373863828 on type 2 diabetes and fasting glucose with path analysis. Results Association of BMI with fasting glucose was greater in those without obesity than in those with obesity. We did not observe evidence of differences by genotype. In the path analysis, the minor allele has direct negative and indirect positive effects on type 2 diabetes risk and fasting glucose, with the indirect effect mediated through a direct positive effect on BMI. Conclusions There may be a stronger effect of BMI on fasting glucose in Polynesians without obesity than in those with obesity. Carrying the rs373863828 minor allele does not decouple higher BMI from odds of type 2 diabetes. Given the current cost of genotyping compared to the accessibility of measuring BMI, including rs373863828 as a clinical predictor of type 2 diabetes may not be indicated.

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A missense variant in CREBRF, rs373863828, is associated with fat-free mass, not fat mass in Samoan infants

Cited by 22 publications

References 28 publications

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

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

The CREBRF diabetes-protective rs373863828-A allele is associated with enhanced early insulin release in men of Māori and Pacific ancestry

CREBRF missense variant rs373863828 has both direct and indirect effects on type 2 diabetes and fasting glucose in Polynesians living in Samoa and Aotearoa New Zealand

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