The Pacific-specific CREBRF rs373863828 allele protects against gestational diabetes mellitus in Māori and Pacific women with obesity

Aims/hypothesis: The CREBRF rs373863828 minor (A) allele is associated with increased BMI but reduced prevalence of type 2 diabetes in Māori and Pacific people. Given the shared aetiology of type 2 diabetes and gestational diabetes mellitus (GDM), we tested for an association between the CREBRF rs373863828 variant and GDM.

Methods: We conducted a prospective cohort study of Māori and Pacific women nested within a nutritional intervention study for pregnant women with obesity. Women were enrolled at 12-17 weeks' gestation and underwent anthropometry and collection of buffy coats for later genetic testing. GDM was diagnosed by 75 g OGTT at 24-28 weeks' gestation using the International Association of Diabetes and Pregnancy Study Groups criteria. Genotyping was performed by real-time PCR with a custom CREBRF rs373863828 probe-set. The association between CREBRF rs373863828 and GDM was analysed separately by ethnic group using logistic regression, with effect estimates combined in a meta-analysis.

Results: Of 112 Māori and Pacific pregnant women with obesity, 31 (28%) carried the CREBRF rs373863828 A allele (A/G or A/A) and 35 (31%) developed GDM. Women who carried the CREBRF rs373863828 A allele did not differ in BMI when compared with non-carriers (G/G). There was a fivefold reduction in the likelihood of GDM per CREBRF rs373863828 A allele (OR 0.19 [95% CI 0.05, 0.69], p = 0.01), independent of age, BMI and family history of diabetes (adjusted OR 0.13 [95% CI 0.03, 0.53], p = 0.004). GDM was diagnosed in 10% and 40% of women with and without the CREBRF rs373863828 A allele, respectively (no woman with the A/A genotype developed GDM).

Conclusions/interpretation: The CREBRF rs373863828 (A) allele is associated with reduced likelihood of GDM in Māori and Pacific women with obesity and may improve GDM risk prediction. Graphical abstract.