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Multivariate analysis of a missense variant in CREBRF reveals associations with measures of adiposity in people of Polynesian ancestries.

ABSTRACT: The minor allele of rs373863828, a missense variant in CREB3 Regulatory Factor, is associated with several cardiometabolic phenotypes in Polynesian peoples. To better understand the variant, we tested the association of rs373863828 with a panel of correlated phenotypes (body mass index [BMI], weight, height, HDL cholesterol, triglycerides, and total cholesterol) using multivariate Bayesian association and network analyses in a Samoa cohort (n = 1632), Aotearoa New Zealand cohort (n = 1419), and combined cohort (n = 2976). An expanded set of phenotypes (adding estimated fat and fat-free mass, abdominal circumference, hip circumference, and abdominal-hip ratio) was tested in the Samoa cohort (n = 1496). In the Samoa cohort, we observed significant associations (log₁₀ Bayes Factor [BF] ≥ 5.0) between rs373863828 and the overall phenotype panel (8.81), weight (8.30), and BMI (6.42). In the Aotearoa New Zealand cohort, we observed suggestive associations (1.5 < log₁₀ BF < 5) between rs373863828 and the overall phenotype panel (4.60), weight (3.27), and BMI (1.80). In the combined cohort, we observed concordant signals with larger log₁₀ BFs. In the Samoa-specific expanded phenotype analyses, we also observed significant associations between rs373863828 and fat mass (5.65), abdominal circumference (5.34), and hip circumference (5.09). Bayesian networks provided evidence for a direct association of rs373863828 with weight and indirect associations with height and BMI.

SUBMITTER: Zhang JZ

PROVIDER: S-EPMC9892232 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Multivariate analysis of a missense variant in CREBRF reveals associations with measures of adiposity in people of Polynesian ancestries.

Zhang Jerry Z JZ Heinsberg Lacey W LW Krishnan Mohanraj M Hawley Nicola L NL Major Tanya J TJ Carlson Jenna C JC Harré Hindmarsh Jennie J Watson Huti H Qasim Muhammad M Stamp Lisa K LK Dalbeth Nicola N Murphy Rinki R Sun Guangyun G Cheng Hong H Naseri Take T Reupena Muagututi'a S MS Kershaw Erin E EE Deka Ranjan R McGarvey Stephen T ST Minster Ryan L RL Merriman Tony R TR Weeks Daniel E DE

Genetic epidemiology 20221109 1

The minor allele of rs373863828, a missense variant in CREB3 Regulatory Factor, is associated with several cardiometabolic phenotypes in Polynesian peoples. To better understand the variant, we tested the association of rs373863828 with a panel of correlated phenotypes (body mass index [BMI], weight, height, HDL cholesterol, triglycerides, and total cholesterol) using multivariate Bayesian association and network analyses in a Samoa cohort (n = 1632), Aotearoa New Zealand cohort (n = 1419), and ...[more]

PMID: 36352773

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Project description:IntroductionThe minor allele of a missense variant, rs373863828, in CREBRF is associated with higher body mass index (BMI), lower fasting glucose, and lower odds of type 2 diabetes. rs373863828 is common in Pacific Island populations (minor allele frequency (MAF) 0.096-0.259) but rare in non-Pacific Island populations (MAF <0.001). We examined the cross-sectional associations between BMI and rs373863828 in type 2 diabetes and fasting glucose with a large sample of adults of Polynesian ancestries from Samoa, American Samoa, and Aotearoa New Zealand, and estimated the direct and indirect (via BMI) effects of rs373863828 on type 2 diabetes and fasting glucose.Research design and methodsWe 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. The regression analyses were completed separately in four samples that were recruited during different time periods between 1990 and 2010 and then the results were meta-analyzed. All samples were pooled for the path analysis.ResultsAssociation of BMI with type 2 diabetes and fasting glucose may be greater in those without obesity (OR=7.77, p=0.015 and β=0.213, p=9.53×10-5, respectively) than in those with obesity (OR=5.01, p=1.12×10-9 and β=0.162, p=5.63×10-6, respectively). We did not observe evidence of differences in the association of BMI with type 2 diabetes or fasting glucose by genotype. In the path analysis, the minor allele has direct negative (lower odds of type 2 diabetes and fasting glucose) and indirect positive (higher odds of type 2 diabetes and fasting glucose) effects on type 2 diabetes risk and fasting glucose, with the indirect effects mediated through a direct positive effect of rs373863828 on BMI.ConclusionsThere may be a stronger effect of BMI on fasting glucose in Polynesian individuals without obesity than in those with obesity. Carrying the rs373863828 minor allele does not decouple higher BMI from higher odds of type 2 diabetes.

Dataset Information

Multivariate analysis of a missense variant in CREBRF reveals associations with measures of adiposity in people of Polynesian ancestries.

Publications

Multivariate analysis of a missense variant in CREBRF reveals associations with measures of adiposity in people of Polynesian ancestries.

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