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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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John M Brehm,
Koichi Hagiwara,
Yohannes Tesfaigzi,
Shannon Bruse,
Thomas J Mariani,
Soumyaroop Bhattacharya,
Nadia Boutaoui, John P Ziniti,
Manuel E Soto-Quiros,
Lydiana Avila, [......],
Augusto A Litonjua,
Francine Jacobson,
Per Bakke,
Amund Gulsvik,
Wayne H Anderson,
David A Lomas,
Erick Forno,
Soma Datta,
Edwin K Silverman,
Juan C Celedón
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ABSTRACT: Traditional genome-wide association studies (GWASs) of large cohorts of subjects with chronic obstructive pulmonary disease (COPD) have successfully identified novel candidate genes, but several other plausible loci do not meet strict criteria for genome-wide significance after correction for multiple testing.
The authors hypothesise that by applying unbiased weights derived from unique populations we can identify additional COPD susceptibility loci. Methods The authors performed a homozygosity haplotype analysis on a group of subjects with and without COPD to identify regions of conserved homozygosity haplotype (RCHHs). Weights were constructed based on the frequency of these RCHHs in case versus controls, and used to adjust the p values from a large collaborative GWAS of COPD.
The authors identified 2318 RCHHs, of which 576 were significantly (p<0.05) over-represented in cases. After applying the weights constructed from these regions to a collaborative GWAS of COPD, the authors identified two single nucleotide polymorphisms (SNPs) in a novel gene (fibroblast growth factor-7 (FGF7)) that gained genome-wide significance by the false discovery rate method. In a follow-up analysis, both SNPs (rs12591300 and rs4480740) were significantly associated with COPD in an independent population (combined p values of 7.9E-7 and 2.8E-6, respectively). In another independent population, increased lung tissue FGF7 expression was associated with worse measures of lung function.
Weights constructed from a homozygosity haplotype analysis of an isolated population successfully identify novel genetic associations from a GWAS on a separate population. This method can be used to identify promising candidate genes that fail to meet strict correction for multiple testing.
Thorax 09/2011; 66(12):1085-90. · 6.84 Impact Factor
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Emily S Wan,
Michael H Cho,
Nadia Boutaoui,
Barbara J Klanderman,
Jody S Sylvia, John P Ziniti,
Sungho Won,
Christoph Lange,
Sreekumar G Pillai,
Wayne H Anderson, [......],
Per S Bakke,
Amund Gulsvik,
Elizabeth A Regan,
James R Murphy,
Barry J Make,
James D Crapo,
Emiel F Wouters,
Bartolome R Celli,
Edwin K Silverman,
Dawn L DeMeo
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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.
American Journal of Respiratory Cell and Molecular Biology 10/2010; 45(2):304-10. · 5.13 Impact Factor
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Michael H Cho,
Nadia Boutaoui,
Barbara J Klanderman,
Jody S Sylvia, John P Ziniti,
Craig P Hersh,
Dawn L DeMeo,
Gary M Hunninghake,
Augusto A Litonjua,
David Sparrow, [......],
John E Hokanson,
James D Crapo,
Xiangyang Kong,
Wayne H Anderson,
Ruth Tal-Singer,
David A Lomas,
Per Bakke,
Amund Gulsvik,
Sreekumar G Pillai,
Edwin K Silverman
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ABSTRACT: We performed a genome-wide association study for chronic obstructive pulmonary disease (COPD) in three population cohorts, including 2,940 cases and 1,380 controls who were current or former smokers with normal lung function. We identified a new susceptibility locus at 4q22.1 in FAM13A and replicated this association in one case-control group (n = 1,006) and two family-based cohorts (n = 3,808) (rs7671167, combined P = 1.2 x 10(-11), combined odds ratio in case-control studies 0.76, 95% confidence interval 0.69-0.83).
Nature Genetics 02/2010; 42(3):200-2. · 35.53 Impact Factor
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Angela J Rogers,
Benjamin A Raby,
John Lima,
Jessica A Lasky-Su,
Amy Murphy,
Ross Lazarus,
Barbara Klanderman,
Jody S Sylvia, John P Ziniti,
Christoph Lange,
Juan C Celedón,
Edwin K Silverman,
Scott T Weiss
American Journal of Respiratory and Critical Care Medicine 01/2010; 181(1):96. · 11.08 Impact Factor
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Angela J Rogers,
Benjamin A Raby,
Jessica A Lasky-Su,
Amy Murphy,
Ross Lazarus,
Barbara J Klanderman,
Jody S Sylvia, John P Ziniti,
Christoph Lange,
Juan C Celedón,
Edwin K Silverman,
Scott T Weiss
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ABSTRACT: Association studies have implicated many genes in asthma pathogenesis, with replicated associations between single-nucleotide polymorphisms (SNPs) and asthma reported for more than 30 genes. Genome-wide genotyping enables simultaneous evaluation of most of this variation, and facilitates more comprehensive analysis of other common genetic variation around these candidate genes for association with asthma.
To use available genome-wide genotypic data to assess the reproducibility of previously reported associations with asthma and to evaluate the contribution of additional common genetic variation surrounding these loci to asthma susceptibility.
Illumina Human Hap 550Kv3 BeadChip (Illumina, San Diego, CA) SNP arrays were genotyped in 422 nuclear families participating in the Childhood Asthma Management Program. Genes with at least one SNP demonstrating prior association with asthma in two or more populations were tested for evidence of association with asthma, using family-based association testing.
We identified 39 candidate genes from the literature, using prespecified criteria. Of the 160 SNPs previously genotyped in these 39 genes, 10 SNPs in 6 genes were significantly associated with asthma (including the first independent replication for asthma-associated integrin beta(3) [ITGB3]). Evaluation of 619 additional common variants included in the Illumina 550K array revealed additional evidence of asthma association for 15 genes, although none were significant after adjustment for multiple comparisons.
We replicated asthma associations for a minority of candidate genes. Pooling genome-wide association study results from multiple studies will increase the power to appreciate marginal effects of genes and further clarify which candidates are true "asthma genes."
American Journal of Respiratory and Critical Care Medicine 04/2009; 179(12):1084-90. · 11.08 Impact Factor
