Genetics, Chronic Obstructive Pulmonary Disease, and the Arrow of Time.
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ABSTRACT:
SUBMITTER: Calverley PMA
PROVIDER: S-EPMC6775883 | biostudies-literature | 2019 Sep
REPOSITORIES: biostudies-literature
Publications
Genetics, Chronic Obstructive Pulmonary Disease, and the Arrow of Time.
Calverley Peter M A PMA Walker Paul P PP
American journal of respiratory and critical care medicine 20190901 6
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Project description:Previous expression quantitative trait loci (eQTL) studies have performed genetic association studies for gene expression, but most of these studies examined lymphoblastoid cell lines from non-diseased individuals. We examined the genetics of gene expression in a relevant disease tissue from chronic obstructive pulmonary disease (COPD) patients to identify functional effects of known susceptibility genes and to find novel disease genes. By combining gene expression profiling on induced sputum samples from 131 COPD cases from the ECLIPSE Study with genomewide single nucleotide polymorphism (SNP) data, we found 4315 significant cis-eQTL SNP-probe set associations (3309 unique SNPs). The 3309 SNPs were tested for association with COPD in a genomewide association study (GWAS) dataset, which included 2940 COPD cases and 1380 controls. Adjusting for 3309 tests (p<1.5e-5), the two SNPs which were significantly associated with COPD were located in two separate genes in a known COPD locus on chromosome 15: CHRNA5 and IREB2. Detailed analysis of chromosome 15 demonstrated additional eQTLs for IREB2 mapping to that gene. eQTL SNPs for CHRNA5 mapped to multiple linkage disequilibrium (LD) bins. The eQTLs for IREB2 and CHRNA5 were not in LD. Seventy-four additional eQTL SNPs were associated with COPD at p<0.01. These were genotyped in two COPD populations, finding replicated associations with a SNP in PSORS1C1, in the HLA-C region on chromosome 6. Integrative analysis of GWAS and gene expression data from relevant tissue from diseased subjects has located potential functional variants in two known COPD genes and has identified a novel COPD susceptibility locus.
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Project description:BackgroundChronic Obstructive Pulmonary Disease (COPD) has a broad spectrum of clinical characteristics. The aetiology of these differences is not well understood. The objective of this study is to assess whether respiratory genetic variants cluster by phenotype and associate with COPD heterogeneity.MethodsWe clustered genome-wide association studies of COPD, lung function, and asthma and phenotypes from the UK Biobank using non-negative matrix factorization. We constructed cluster-specific genetic risk scores and tested these scores for association with phenotypes in non-Hispanic white subjects in the COPDGene study.FindingsWe identified three clusters from 482 variants and 44 traits from genetic associations in 379,337 UK Biobank participants. Variants from asthma, COPD, and lung function were found in all three clusters. Clusters displayed varying effects on white blood cell counts, height, and body mass index (BMI)-related phenotypes in the UK Biobank. In the COPDGene cohort, cluster-specific genetic risk scores were associated with differences in steroid use, BMI, lymphocyte counts, and chronic bronchitis, as well as variations in gene and protein expression.InterpretationOur results suggest that multi-phenotype analysis of obstructive lung disease-related risk variants may identify genetically driven phenotypic patterns in COPD.FundingMHC was supported by R01HL149861, R01HL135142, R01HL137927, R01HL147148, and R01HL089856. HA and HJ were supported by ANR-20-CE36-0009-02 and ANR-16-CONV-0005. The COPDGene study (NCT00608764) is supported by grants from the NHLBI (U01HL089897 and U01HL089856), by NIH contract 75N92023D00011, and by the COPD Foundation through contributions made to an Industry Advisory Committee that has included AstraZeneca, Bayer Pharmaceuticals, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer and Sunovion.
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Project description:Chronic obstructive pulmonary disease (COPD) Metagenome
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Project description:BackgroundSmoking is the principal modifiable environmental risk factor for chronic obstructive pulmonary disease (COPD) which affects 300 million people and is the 3rd leading cause of death worldwide. Most of the genetic studies of smoking have relied on self-reported smoking status which is vulnerable to reporting and recall bias. Using data from the Lung Health Study (LHS), we sought to identify genetic variants associated with quantitative smoking and cessation in individuals with mild to moderate COPD.MethodsThe LHS is a longitudinal multicenter study of mild-to-moderate COPD subjects who were all smokers at recruitment. We performed genome-wide association studies (GWASs) for salivary cotinine (n = 4024), exhaled carbon monoxide (eCO) (n = 2854), cigarettes per day (CPD) (n = 2706) and smoking cessation at year 5 follow-up (n = 717 quitters and 2175 smokers). The GWAS analyses were adjusted for age, gender, and genetic principal components.ResultsFor cotinine levels, SNPs near UGT2B10 gene achieved genome-wide significance (i.e. P < 5 × 10- 8) with top SNP rs10023464, P = 1.27 × 10- 11. For eCO levels, one significant SNP was identified which mapped to the CHRNA3 gene (rs12914385, P = 2.38 × 10- 8). A borderline region mapping to KCNMA1 gene was associated with smoking cessation (rs207675, P = 5.95 × 10- 8). Of the identified loci, only the CHRNA3/5 locus showed significant associations with lung function but only in heavy smokers. No regions met genome-wide significance for CPD.ConclusionThe study demonstrates that using objective measures of smoking such as eCO and/or salivary cotinine can more precisely capture the genetic contribution to multiple aspects of smoking behaviour. The KCNMA1 gene association with smoking cessation may represent a potential therapeutic target and warrants further studies.Trial registrationThe Lung Health Study ClinicalTrials.gov Identifier: NCT00000568 . Date of registration: October 28, 1999.
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