DNA Sequence Variation in ACVR1C Encoding the Activin Receptor-Like Kinase 7 Influences Body Fat Distribution and Protects Against Type 2 Diabetes
DNA Sequence Variation in ACVR1C Encoding the Activin Receptor-Like Kinase 7 Influences Body Fat Distribution and Protects Against Type 2 Diabetes
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DOI：
10.2337/db18-0857
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发表时间：
2019-01-01
期刊：
影响因子：
7.7
通讯作者：
Kathiresan, Sekar
中科院分区：
文献类型：
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作者：
Emdin, Connor A.;Khera, Amit V.;Kathiresan, Sekar
遗传倾向于较高的腰臀比调整BMI（WHRadjBMI），身体脂肪分布的措施，与2型糖尿病的风险增加。我们在UK Biobank（405，569人）中进行了一项编码变异的外显子组关联研究，以确定降低WHRadjBMI并预防2型糖尿病的变异。我们在ACVR 1C基因中发现了四种变体，（编码在脂肪细胞和胰腺β细胞上表达的激活素受体样激酶7受体），其独立地与降低的WHRadjBMI相关：Asn150His（-0.09 SD，P = 3.4 x 10（-17）），Ile 195 Thr（-0.15 SD，P = 1.0 x 10（-9）），Ile482Val（-0.019 SD，P = 1.6 x 10（-5））和rs72927479（-0.035 SD，P = 2.6 x 10（-12））。这些变异体的携带者在DEXA成像中表现出腹部脂肪百分比降低。合并所有四种变异，通过ACVR 1C，WHRadjBMI降低0.2 SD与2型糖尿病风险降低30%相关（比值比[OR] 0.70，95% CI 0.63，0.77; P = 5.6 x 10（-13））。在对来自55，516名个体的外显子组序列的分析中，ACVR 1C中预测破坏性变体的携带者患2型糖尿病的风险降低54%（OR 0.46，95%CI 0.27，0.81; P = 0.006）。这些发现表明，预测导致ACVR 1C基因功能丧失的变异影响体脂分布并保护2型糖尿病。
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 beta-cells), which independently associated with reduced WHRadjBMI: Asn150His (-0.09 SD, P = 3.4 x 10(-17)), Ile195Thr (-0.15 SD, P = 1.0 x 10(-9)), Ile482Val (-0.019 SD, P = 1.6 x 10(-5)), and rs72927479 (-0.035 SD, P = 2.6 x 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 x 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.