Peter Inga, Papandonatos George D, Belalcazar L Maria, Yang Yao, Erar Bahar, Jakicic John M, Unick Jessica L, Balasubramanyam Ashok, Lipkin Edward W, Delahanty Linda M, Wagenknecht Lynne E, Wing Rena R, McCaffery Jeanne M, Huggins Gordon S
1Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY; 2Center for Statistical Sciences, Brown University, Providence, RI; 3Department of Medicine, University of Texas Medical Branch, Galveston, TX; 4Department of Health and Physical Activity, Physical Activity and Weight Management Research Center, University of Pittsburgh, Pittsburgh, PA; 5Weight Control and Diabetes Research Center, Department of Psychiatry and Human Behavior, The Miriam Hospital and Brown Medical School, Providence, RI; 6Translational Metabolism Unit, Diabetes Research Center, Division of Diabetes, Endocrinology and Metabolism, Baylor College of Medicine, Houston, TX; 7Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA; 8Diabetes Research Center, Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Boston, MA; 9Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC; and 10Molecular Cardiology Research Institute, Center for Translational Genomics, Tufts Medical Center and Tufts University, Boston, MA.
Med Sci Sports Exerc. 2014 Feb;46(2):302-11. doi: 10.1249/MSS.0b013e3182a66155.
Numerous prospective studies indicate that improved cardiorespiratory fitness reduces type 2 diabetes risk and delays disease progression. We hypothesized that genetic variants modify fitness response to an intensive lifestyle intervention (ILI) in the Action for Health in Diabetes (Look AHEAD) randomized clinical trial, aimed to detect whether ILI will reduce cardiovascular events in overweight/obese subjects with type 2 diabetes compared with a standard of care.
Polymorphisms in established fitness genes and in all loci assayed on the Illumina CARe iSelect chip were examined as predictors of change in MET level, estimated using a treadmill test, in response to a 1-yr intervention in 3899 participants.
We identified a significant signal in previously reported fitness-related gene RUNX1 that was associated with 1-yr METs response in ILI (0.19 ± 0.04 MET less improvement per minor allele copy; P = 1.9 × 10(-5)) and genotype-intervention interaction (P = 4.8 × 10(-3)). In the chipwide analysis, FKBP7 rs17225700 showed a significant association with ILI response among subjects not receiving beta-blocker medications (0.47 ± 0.09 METs less improvement; P = 5.3 × 10(-5)) and genotype-treatment interaction (P = 5.3 × 10(-7)). The Gene Relationships Among Implicated Loci pathway-based analysis identified connections between associated genes, including those influencing vascular tone, muscle contraction, cardiac energy substrate dynamics, and muscle protein synthesis.
This is the first study to identify genetic variants associated with fitness responses to a randomized lifestyle intervention in overweight/obese diabetic individuals. RUNX1 and FKBP7, involved in erythropoesis and muscle protein synthesis, respectively, are related to change in cardiorespiratory fitness in response to exercise.
众多前瞻性研究表明，改善心肺适能可降低2型糖尿病风险并延缓疾病进展。我们假设在糖尿病健康行动（Look AHEAD）随机临床试验中，基因变异会改变对强化生活方式干预（ILI）的适能反应，该试验旨在检测与标准治疗相比，ILI是否会降低超重/肥胖2型糖尿病患者的心血管事件发生率。
在3899名参与者中，对既定适能基因以及Illumina CARe iSelect芯片上检测的所有位点的多态性进行检测，作为使用跑步机测试估计的代谢当量（MET）水平变化的预测指标，以反映1年干预后的情况。
我们在先前报道的与适能相关的基因RUNX1中发现了一个显著信号，该信号与ILI中1年的MET反应相关（每个次要等位基因拷贝的改善减少0.19±0.0 MET；P = 1.9×10⁻⁵）以及基因型 - 干预相互作用（P = 4.8×10⁻³）。在全芯片分析中，FKBP7 rs17225700在未接受β受体阻滞剂药物治疗的受试者中显示出与ILI反应的显著关联（改善减少0.47±0.09 MET；P = 5.3×10⁻⁵）以及基因型 - 治疗相互作用（P = 5.3×10⁻⁷）。基于牵连位点间基因关系途径的分析确定了相关基因之间的联系，包括那些影响血管张力、肌肉收缩、心脏能量底物动态和肌肉蛋白质合成的基因。
这是第一项识别超重/肥胖糖尿病个体对随机生活方式干预的适能反应相关基因变异的研究。分别参与红细胞生成和肌肉蛋白质合成的RUNX1和FKBP7与运动引起的心肺适能变化有关。
