Southwest American Indians (SAI) suffer from a high obesity prevalence. We previously reported that rs7238987, in cytochrome B5 type A (CYB5A), strongly associated with increased body mass index (BMI) in a population-based study of SAI. CYB5A plays a role in fatty acid oxidation (FAO) and reductions in FAO have been linked to weight gain. However, in vitro studies did not confirm a functional effect of this variant. Therefore, the goal of the current study was to assess variation across the entire CYB5A locus to identify the causal variant contributing to obesity in this population. Genotypic data from a custom Axiom genotyping array on 7,700 SAI was merged with whole-genome sequence data from 335 SAI to impute variation within and 10,000 bp surrounding the CYB5A gene. This region contained 316 variants with a minor allele frequency >0.01; 3 variants had a Combined Annotation Dependent Depletion (CADD) score >10 (top 10% most likely to be deleterious) and a BMI association P ≤ 0.001 (adjusted for age, sex, birth year and the first 5 genetic principle components). Among these potentially deleterious variants, the obesity-risk T-allele in rs548402150, also significantly associated (P = 0.00003) with decreased CYB5A expression in skeletal muscle from biopsy data (n=207). Therefore, rs548402150 was prioritized for functional studies. This C/T variation falls within a CTCF consensus site in the 5’-UTR, which could have the ability to effect gene expression levels. In vitro luciferase reporter assays were used to assess altered promoter activity in human skeletal muscle cells. A 30% decrease in luciferase expression was identified for the promoter carrying the obesity-risk T-allele compared to the non-risk C-allele (P = 0.003).

In summary, the further exploration of CYB5A using imputed data has identified a potential casual variant for the observed decreased CYB5A expression and increased risk of obesity in this population.


S.E. Day: None. M. Traurig: None. P. Piaggi: None. P. Kumar: None. S. Kobes: None. R.L. Hanson: None. C. Bogardus: None. L. Baier: None.

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