271-OR: Whole-Exome Sequence Identifies Potentially Functional Rare Variants in Bardet-Biedl Syndrome (BBS) Genes that Associate with Obesity in American Indians

Abstract

American Indians suffer from a high prevalence of obesity. Although their obesity is typically polygenic in nature, we are systematically analyzing known monogenic obesity genes in a population-based sample of Pima Indians. Previously, we have reported that 3% of this population carries functional mutations in MC4R. The goal of the current study is to determine whether variation in any of the 21 known BBS genes also contribute to obesity in this population. Analysis of whole exome sequence data from 6,809 Pima Indians (44.8% male; mean±SD age 34.8 ± 16.0 years; mean±SD maximum body mass index (BMI) 36.2 ± 8.8 kg/m2; 31.9% had T2D) identified 1,726 variants in the 21 BBS genes, of which 273 variants had a Combined Annotation Dependent Depletion (CADD) score >20 (top 1% most likely to be deleterious). Among these potentially deleterious variants, 32 were exclusive to, or enriched in, obese subjects (mean BMI for carriers >40). Five of the 32 variants were in the BBS9 gene and these were prioritized for functional studies. BBS mutations may impact obesity via leptin signaling, where BBS gene dysfunction has led to increased food intake. Therefore, in vitro luciferase reporter assays targeting STAT3 transcriptional activity were used to assess alterations in leptin signaling by the BBS variants. Analysis of a Thr549Ile (rs59252892) in BBS9 (mean BMI of Ile allele carriers was 41.3 ± 12.4 kg/m2 vs. 36.4 ± 8.8 kg/m2 for non-carriers, P=0.0008) showed that the Ile allele had a 28% increase in leptin signaling activity compared to the Thr allele (P=0.006, 5 experiments). Moreover, western blot analysis showed that the Ile allele had a 19% increase in STAT3 phosphorylation compared to the Thr allele. Comparable in vitro results were observed with a S545G, but not a K810E or L665F in BBS9. In summary, whole exome sequencing in Pima Indians has identified potentially functional variants in BBS9 that may increase risk for obesity through leptin signaling. Disclosure S.E. Day: None. Y.L. Muller: None. S. Kobes: None. H. Kim: Employee; Self; Regeneron Pharmaceuticals. C.V. Van Hout: Employee; Self; Regeneron Pharmaceuticals. N. Gosalia: Employee; Self; Regeneron Pharmaceuticals. B. Ye: Employee; Self; Regeneron Pharmaceuticals. A.R. Shuldiner: Employee; Self; Regeneron Pharmaceuticals. Stock/Shareholder; Self; Rhythm Pharmaceuticals, Inc. R.L. Hanson: None. C. Koroglu Altok: None. C. Bogardus: None. L.J. Baier: None.