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Genome-wide association analysis of body mass in chronic obstructive pulmonary disease.

ABSTRACT: 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.

SUBMITTER: Wan ES

PROVIDER: S-EPMC3266061 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Genome-wide association analysis of body mass in chronic obstructive pulmonary disease.

Wan Emily S ES Cho Michael H MH Boutaoui Nadia N Klanderman Barbara J BJ Sylvia Jody S JS Ziniti John P JP Won Sungho S Lange Christoph C Pillai Sreekumar G SG Anderson Wayne H WH Kong Xiangyang X Lomas David A DA Bakke Per S PS Gulsvik Amund A Regan Elizabeth A EA Murphy James R JR Make Barry J BJ Crapo James D JD Wouters Emiel F EF Celli Bartolome R BR Silverman Edwin K EK DeMeo Dawn L DL

American journal of respiratory cell and molecular biology 20101029 2

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 de ...[more]

PMID: 21037115

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Project description:BACKGROUND:The genetic risk factors for susceptibility to chronic obstructive pulmonary disease (COPD) are still largely unknown. Additional genetic variants are likely to be identified by genome-wide association studies in larger cohorts or specific subgroups. We sought to identify risk loci for moderate to severe and severe COPD with data from several cohort studies. METHODS:We combined genome-wide association analysis data from participants in the COPDGene study (non-Hispanic white and African-American ethnic origin) and the ECLIPSE, NETT/NAS, and Norway GenKOLS studies (self-described white ethnic origin). We did analyses comparing control individuals with individuals with moderate to severe COPD and with a subset of individuals with severe COPD. Single nucleotide polymorphisms yielding a p value of less than 5?×?10(-7) in the meta-analysis at loci not previously described were genotyped in individuals from the family-based ICGN study. We combined results in a joint meta-analysis (threshold for significance p<5?×?10(-8)). FINDINGS:Analysis of 6633 individuals with moderate to severe COPD and 5704 control individuals confirmed association at three known loci: CHRNA3 (p=6·38?×?10(-14)), FAM13A (p=1·12?×?10(-14)), and HHIP (p=1·57?×?10(-12)). We also showed significant evidence of association at a novel locus near RIN3 (p=5·25?×?10(-9)). In the overall meta-analysis (ie, including data from 2859 ICGN participants), the association with RIN3 remained significant (p=5·4?×?10(-9)). 3497 individuals were included in our analysis of severe COPD. The effect estimates for the loci near HHIP and CHRNA3 were significantly stronger in severe disease than in moderate to severe disease (p<0·01). We also identified associations at two additional loci: MMP12 (overall joint meta-analysis p=2·6?×?10(-9)) and TGFB2 (overall joint meta-analysis p=8·3?×?10(-9)). INTERPRETATION:We have confirmed associations with COPD at three known loci and identified three new genome-wide significant associations. Genetic variants other than in ?-1 antitrypsin increase the risk of COPD. FUNDING:US National Heart, Lung, and Blood Institute; the Alpha-1 Foundation; the COPD Foundation through contributions from AstraZeneca, Boehringer Ingelheim, Novartis, and Sepracor; GlaxoSmithKline; Centers for Medicare and Medicaid Services; Agency for Healthcare Research and Quality; and US Department of Veterans Affairs.

Dataset Information

Genome-wide association analysis of body mass in chronic obstructive pulmonary disease.

Publications

Genome-wide association analysis of body mass in chronic obstructive pulmonary disease.

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