Functional Characterization of CYP26B1 Short Isoform as a Novel Locus for Obesity in Indigenous Americans From Arizona

Objective: To identify heritable factors that affect BMI among Indigenous Americans, we previously conducted a genome-wide association study using 7.9 million imputed genetic variants from 6789 participants. This study sought to identify a mechanistic link between variants with the strongest association with BMI and adipocyte metabolism. Methods: Variants with the strongest association with BMI (rs114857151, rs187498396, and rs189879565; r2 = 0.99, 2.7% increase in BMI per risk allele, p = 4 × 10-7, adjusted for age, sex, birth year, and the first five genetic principal components) were functionally analyzed using luciferase assays. Results: These variants map to CYP26B1, which encodes an enzyme involved in retinoic acid (RA) metabolism. In vitro studies showed that the haplotype with the three risk (higher BMI) variants had a 23% decrease in CYP26B1 transcript variant 3 (TV3) promoter activity. RA response element reporter assays showed that the Cyp26b1 TV3 isoform might be important for RA homeostasis in adipocytes. Cyp26b1 TV3 knockdown in mouse OP9 adipocytes resulted in increased Aldh1a1 expression. Conclusion: Alleles carrying these three variants may have reduced expression of CYP26B1 TV3 which in turn influences RA signaling and adipocyte metabolism, providing a possible mechanistic link between CYP26B1 variation and BMI.