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Michael H Cho,
Peter J Castaldi,
Emily S Wan,
Mateusz Siedlinski,
Craig P Hersh,
Dawn L Demeo,
Blanca E Himes,
Jody S Sylvia,
Barbara J Klanderman,
John P Ziniti, [......],
Peter M A Calverley,
Bartolome Celli,
Courtney Crim,
Stephen Rennard,
Emiel Wouters,
Per Bakke,
Amund Gulsvik,
James D Crapo,
Terri H Beaty,
Edwin K Silverman
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ABSTRACT: The genetic risk factors for chronic obstructive pulmonary disease (COPD) are still largely unknown. To date, genome-wide association studies (GWASs) of limited size have identified several novel risk loci for COPD at CHRNA3/CHRNA5/IREB2, HHIP and FAM13A; additional loci may be identified through larger studies. We performed a GWAS using a total of 3499 cases and 1922 control subjects from four cohorts: the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE); the Normative Aging Study (NAS) and National Emphysema Treatment Trial (NETT); Bergen, Norway (GenKOLS); and the COPDGene study. Genotyping was performed on Illumina platforms with additional markers imputed using 1000 Genomes data; results were summarized using fixed-effect meta-analysis. We identified a new genome-wide significant locus on chromosome 19q13 (rs7937, OR = 0.74, P = 2.9 × 10(-9)). Genotyping this single nucleotide polymorphism (SNP) and another nearby SNP in linkage disequilibrium (rs2604894) in 2859 subjects from the family-based International COPD Genetics Network study (ICGN) demonstrated supportive evidence for association for COPD (P = 0.28 and 0.11 for rs7937 and rs2604894), pre-bronchodilator FEV(1) (P = 0.08 and 0.04) and severe (GOLD 3&4) COPD (P = 0.09 and 0.017). This region includes RAB4B, EGLN2, MIA and CYP2A6, and has previously been identified in association with cigarette smoking behavior.
Human Molecular Genetics 11/2011; 21(4):947-57. · 7.64 Impact Factor
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Nancy L Saccone,
Robert C Culverhouse,
Tae-Hwi Schwantes-An,
Dale S Cannon,
Xiangning Chen,
Sven Cichon,
Ina Giegling,
Shizhong Han,
Younghun Han,
Kaisu Keskitalo-Vuokko, [......],
Mark F Leppert,
Ming D Li,
Pamela A F Madden,
Markus M Nöthen, Sreekumar Pillai,
Marcella Rietschel,
Dan Rujescu,
Ann Schwartz,
Christopher I Amos,
Laura J Bierut
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ABSTRACT: Recently, genetic association findings for nicotine dependence, smoking behavior, and smoking-related diseases converged to implicate the chromosome 15q25.1 region, which includes the CHRNA5-CHRNA3-CHRNB4 cholinergic nicotinic receptor subunit genes. In particular, association with the nonsynonymous CHRNA5 SNP rs16969968 and correlates has been replicated in several independent studies. Extensive genotyping of this region has suggested additional statistically distinct signals for nicotine dependence, tagged by rs578776 and rs588765. One goal of the Consortium for the Genetic Analysis of Smoking Phenotypes (CGASP) is to elucidate the associations among these markers and dichotomous smoking quantity (heavy versus light smoking), lung cancer, and chronic obstructive pulmonary disease (COPD). We performed a meta-analysis across 34 datasets of European-ancestry subjects, including 38,617 smokers who were assessed for cigarettes-per-day, 7,700 lung cancer cases and 5,914 lung-cancer-free controls (all smokers), and 2,614 COPD cases and 3,568 COPD-free controls (all smokers). We demonstrate statistically independent associations of rs16969968 and rs588765 with smoking (mutually adjusted p-values<10(-35) and <10(-8) respectively). Because the risk alleles at these loci are negatively correlated, their association with smoking is stronger in the joint model than when each SNP is analyzed alone. Rs578776 also demonstrates association with smoking after adjustment for rs16969968 (p<10(-6)). In models adjusting for cigarettes-per-day, we confirm the association between rs16969968 and lung cancer (p<10(-20)) and observe a nominally significant association with COPD (p = 0.01); the other loci are not significantly associated with either lung cancer or COPD after adjusting for rs16969968. This study provides strong evidence that multiple statistically distinct loci in this region affect smoking behavior. This study is also the first report of association between rs588765 (and correlates) and smoking that achieves genome-wide significance; these SNPs have previously been associated with mRNA levels of CHRNA5 in brain and lung tissue.
PLoS Genetics 08/2010; 6(8). · 8.69 Impact Factor
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ABSTRACT: The authors of previous reports have suggested that women are more susceptible to cigarette smoke and to an airway-predominant COPD phenotype rather than an emphysema-predominant COPD phenotype. The purpose of this study was to test for sex differences in COPD phenotypes by using high-resolution CT (HRCT) scanning in male and female smokers with and without COPD.
All subjects completed spirometry and answered an epidemiologic respiratory questionnaire. Inspiratory HRCT scans were obtained on 688 smokers enrolled in a family-based study of COPD. Emphysema was assessed by using a density mask with a cutoff of -950 Hounsfield units to calculate the low-attenuation area percentage (LAA%) and by the fractal value D, which is the slope of a power law analysis defining the relationship between the number and size of the emphysematous lesions. Airway wall thickness was assessed by calculating the square root of the airway wall area (SQRTWA) and the percentage of the total airway area taken by the airway wall (WA%) relative to the internal perimeter.
Women had a similar FEV(1) (women, 65.5% +/- 31.9% predicted; men, 62.1% +/- 30.4% predicted; p = 0.16) but fewer pack-years of cigarette smoking (women, 37.8 +/- 19.7 pack-years; men, 47.8 +/- 27.4 pack-years; p < 0.0001). Men had a greater LAA% (24% +/- 12% vs 20% +/- 11%, respectively; p < 0.0001) and larger emphysematous spaces than women, and these differences persisted after adjusting for covariates (weight, pack-years of smoking, current smoking status, center of enrollment, and FEV(1) percent predicted; p = 0.0006). Women had a smaller SQRTWA and WA% after adjusting for covariates (p < 0.0001).
Male smokers have more emphysema than female smokers, but female smokers do not show increased wall thickness compared with men.
Chest 08/2009; 136(6):1480-8. · 5.25 Impact Factor
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Proceedings of the American Thoracic Society 09/2006; 3(6):533.
