| Title: | DNA Sequence Variation in ACVR1C Encoding the Activin-Receptor Like Kinase 7 Influences Body Fat Distribution and Protects Against Type 2 Diabetes |
| Journal: | Diabetes |
| Published: | 2 Nov 2018 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/30389748/ |
| DOI: | https://doi.org/10.2337/db18-0857 |
| URL: | https://diabetes.diabetesjournals.org/content/diabetes/68/1/226.full.pdf |
| Citations: | 35 (13 in last 2 years) as of 8 Aug 2024 |
Publication 4716
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Abstract
A genetic predisposition to higher waist-to-hip ratio adjusted for BMI (WHRadjBMI), a measure of body fat distribution, associates with increased risk for type 2 diabetes. We conducted an exome-wide association study of coding variation in UK Biobank (405,569 individuals) to identify variants that lower WHRadjBMI and protect against type 2 diabetes. We identified four variants in the gene ACVR1C (encoding the activin receptor-like kinase 7 receptor expressed on adipocytes and pancreatic β-cells), which independently associated with reduced WHRadjBMI: Asn150His (-0.09 SD, P = 3.4 × 10-17), Ile195Thr (-0.15 SD, P = 1.0 × 10-9), Ile482Val (-0.019 SD, P = 1.6 × 10-5), and rs72927479 (-0.035 SD, P = 2.6 × 10-12). Carriers of these variants exhibited reduced percent abdominal fat in DEXA imaging. Pooling across all four variants, a 0.2 SD decrease in WHRadjBMI through ACVR1C was associated with a 30% lower risk of type 2 diabetes (odds ratio [OR] 0.70, 95% CI 0.63, 0.77; P = 5.6 × 10-13). In an analysis of exome sequences from 55,516 individuals, carriers of predicted damaging variants in ACVR1C were at 54% lower risk of type 2 diabetes (OR 0.46, 95% CI 0.27, 0.81; P = 0.006). These findings indicate that variants predicted to lead to loss of ACVR1C gene function influence body fat distribution and protect from type 2 diabetes.</p>
8 Keywords
- Activin Receptors, Type I
- Algorithms
- Diabetes Mellitus, Type 2
- Exome
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Humans
- Sequence Analysis, DNA
25 Authors
- Connor A Emdin
- Amit V Khera
- Krishna Aragam
- Mary Haas
- Mark Chaffin
- Derek Klarin
- Pradeep Natarajan
- Alexander Bick
- Seyedeh M Zekavat
- Akihiro Nomura
- Diego Ardissino
- James G Wilson
- Heribert Schunkert
- Ruth McPherson
- Hugh Watkins
- Roberto Elosua
- Matthew J Bown
- Nilesh J Samani
- Usman Baber
- Jeanette Erdmann
- Namrata Gupta
- John Danesh
- Danish Saleheen
- Stacey Gabriel
- Sekar Kathiresan
Enabling scientific discoveries that improve human health