Channing Laboratory, Boston, Massachusetts, USA.
Am J Respir Cell Mol Biol. 2011 Aug;45(2):304-10. doi: 10.1165/rcmb.2010-0294OC. Epub 2010 Oct 29.
Cachexia, whether assessed by body mass index (BMI) or fat-free mass index (FFMI), affects a significant proportion of patients with chronic obstructive pulmonary disease (COPD), and is an independent risk factor for increased mortality, increased emphysema, and more severe airflow obstruction. The variable development of cachexia among patients with COPD suggests a role for genetic susceptibility. The objective of the present study was to determine genetic susceptibility loci involved in the development of low BMI and FFMI in subjects with COPD. A genome-wide association study (GWAS) of BMI was conducted in three independent cohorts of European descent with Global Initiative for Chronic Obstructive Lung Disease stage II or higher COPD: Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-Points (ECLIPSE; n = 1,734); Norway-Bergen cohort (n = 851); and a subset of subjects from the National Emphysema Treatment Trial (NETT; n = 365). A genome-wide association of FFMI was conducted in two of the cohorts (ECLIPSE and Norway). In the combined analyses, a significant association was found between rs8050136, located in the first intron of the fat mass and obesity-associated (FTO) gene, and BMI (P = 4.97 × 10(-7)) and FFMI (P = 1.19 × 10(-7)). We replicated the association in a fourth, independent cohort consisting of 502 subjects with COPD from COPDGene (P = 6 × 10(-3)). Within the largest contributing cohort of our analysis, lung function, as assessed by forced expiratory volume at 1 second, varied significantly by FTO genotype. Our analysis suggests a potential role for the FTO locus in the determination of anthropomorphic measures associated with COPD.
无论采用体重指数（BMI）还是去脂体重指数（FFMI）评估，恶病质都会影响相当一部分慢性阻塞性肺疾病（COPD）患者，并且是死亡率增加、肺气肿加重和气流阻塞更严重的独立危险因素。COPD 患者恶病质的不同发展表明遗传易感性起作用。本研究的目的是确定与 COPD 患者 BMI 和 FFMI 降低相关的遗传易感性基因座。对具有 GOLD Ⅱ级或更高 COPD 的三个欧洲血统独立队列（评估 COPD 纵向变化以确定预测替代终点的研究（ECLIPSE；n = 1734）、挪威-卑尔根队列（n = 851）和国家肺气肿治疗试验（NETT；n = 365）的亚组）进行了 BMI 的全基因组关联研究（GWAS）。在 ECLIPSE 和挪威这两个队列中进行了 FFMI 的全基因组关联研究。在联合分析中，发现 rs8050136 与 BMI（P = 4.97×10(-7)) 和 FFMI（P = 1.19×10(-7)) 之间存在显著关联，该基因位于脂肪量和肥胖相关基因（FTO）的第一内含子中。我们在由 502 名 COPD 患者组成的第四个独立队列 COPDGene 中复制了该关联（P = 6×10(-3))。在我们分析的最大贡献队列中，FTO 基因型显著影响一秒用力呼气量等肺功能。我们的分析表明 FTO 基因座在确定与 COPD 相关的人体测量指标方面具有潜在作用。
