TY - JOUR T1 - <em>CREBRF</em> missense variant rs373863828 has both direct and indirect effects on type 2 diabetes and fasting glucose in Polynesian peoples living in Samoa and Aotearoa New Zealand JF - BMJ Open Diabetes Research &amp; Care JO - BMJ Open Diab Res Care DO - 10.1136/bmjdrc-2021-002275 VL - 10 IS - 1 SP - e002275 AU - Emily M Russell AU - Jenna C Carlson AU - Mohanraj Krishnan AU - Nicola L Hawley AU - Guangyun Sun AU - Hong Cheng AU - Take Naseri AU - Muagututi‘a Sefuiva Reupena AU - Satupa‘itea Viali AU - John Tuitele AU - Tanya J Major AU - Iva Miljkovic AU - Tony R Merriman AU - Ranjan Deka AU - Daniel E Weeks AU - Stephen T McGarvey AU - Ryan L Minster Y1 - 2022/02/01 UR - http://drc.bmj.com/content/10/1/e002275.abstract N2 - Introduction The 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 &lt;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 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. 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.Results Association 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.Conclusions There 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.Data are available in a public, open access repository. Data are available upon reasonable request. No data are available. The 2010 sample data from Samoa examined in this study are available from dbGaP (accession number: phs000914.v1.p1). The 1991–1995 and 2002–2003 sample data from Samoa and American Samoa are not available because participants did not consent to data sharing when enrolled. Sample data from Aotearoa New Zealand are not publicly available owing to consent restrictions, but can be requested from author TRM (https://orcid.org/0000-0003-0844-8726) under an appropriate arrangement. ER -