Introduction and Objective: Obesity is a serious health issue for Indigenous Americans residing in Arizona and genetic factors are believed to play a role in the development of this chronic disease. The aim of this study was to identify and mechanistically study variants that associate with BMI. We identified 3 variants associated with BMI located in predicted transcriptional regulatory regions in CYP26B1 transcript variant 3 (TV3), an enzyme involved in retinoic acid (RA) metabolism.Methods: We previously conducted a GWAS using 7.9M imputed genetic variants from 6789 Indigenous Americans and BMI measured at age ≥15 years. The effects of the CYP26B1 variants on transcription regulation were analyzed using luciferase assay with CYP26B1 promoter vectors containing selected variants. OP9 mouse adipocytes were used to examine the effects of overexpression and ASO-mediated knockdown of Cyp26b1 TV3 on RA metabolism and expression of genes involved in lipid metabolism and mitochondrial function.Results: The strongest associations with BMI were 3 variants, rs114857151, rs187498396, and rs189879565, in high LD (r2≥0.99) located in potential transcriptional regulatory regions in CYP26B1 (P=4×10-7, adjusted for age, sex, birthyear, and the first 5 genetic principal components). These variants are enriched in this indigenous cohort (MAF=0.21) compared to the gnomAD dataset (0.028, 0.0078, and 0.0079 respectively). Luciferase assays showed that the BMI risk haplotype for 3 variants had a 22% decrease in activity for the CYP26B1 TV3 promotor (P=0.01). TV3 codes for a truncated CYP26B1 enzyme and luciferase assay using a RARE reporter vector showed that TV3 can regulate RA-dependent transcription. Cyp26b1 TV3 knockdown during OP9 adipogenesis treated with 1µM RA resulted in upregulation of Aldh1a1 and downregulation of Mcad, Scd1 and Ucp1.Conclusion: This study identified a novel BMI gene, CYP26B1 TV3, and suggests that reduced CYP26B1 TV3 levels might influence RA signaling, lipid metabolism, and energy expenditure providing a mechanistic link between CYP26B1 variations and BMI.
F.F. Khan: None. K. Freeland: None. M. Traurig: None. Y.L. Muller: None. L. Baier: None.
Source link
Leave a Reply