Computational protocol: Association of IREB2 and CHRNA3 polymorphisms with airflow obstruction in severe alpha-1 antitrypsin deficiency

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Protocol publication

[…] Two SNPs (rs8034191 and rs1051730) in chromosome 15 were selected from the previous GWA in COPD []. Additionally, 7 SNPs in IREB2 were selected using pairwise linkage disequilibrium (LD)-tagging in Tagger with a minimum minor allele frequency of 0.05 and r2-threshold of 0.8 []. SNPs were genotyped using Sequenom (San Diego, CA) assays in the AAT Genetic Modifiers Study. All family data were evaluated for familial inconsistencies using the PEDCHECK program [].In UK AATD National Registry study, genotyping was carried out using TaqMan┬« technologies (Applied Biosystems, UK) on an ABI7900 HT for 3 SNPs associated in the test dataset (rs2568494, IREB2; rs8034191, LOC123688; rs1051730, CHRNA3). All genotyping assays were pre-validated by the suppliers, and all plates included appropriate negative controls. [...] Hardy-Weinberg equilibrium was assessed using goodness of fit tests. Pre- and post-bronchodilator FEV1 percent of predicted and pre- and post-bronchodilator FEV1/FVC ratio were analyzed as quantitative phenotypes. Family-based association analysis was performed using PBAT software version 3.6 [] assuming additive genetic models, adjusting for pack-years and pack-years2 of cigarette smoking, under the null hypothesis of no linkage and no association in the AAT Genetic Modifiers Study. In addition to the overall model, we evaluated gender-stratified models and models that included a SNP-by-smoking or a SNP-by-gender interaction term. Haplotype analysis was performed using 8, 4, 3, 2 SNP adjacent sliding windows in PBAT.In the UK AATD National Registry study, data were analyzed using SPSS (version 16, Chicago: SPSS Inc). Quantitative genetic association analysis was carried out for FEV1 and FEV1/FVC using general linear models, adjusting for age, gender and smoke exposure (as pack-years and pack-years2). Logistic regression models were used for the presence of emphysema or COPD (defined as post bronchodilator FEV1/FVC < 0.7) accounting for covariates as before. Additive models were assumed for all SNPs. Gender stratification and SNP-by-gender and SNP-by-smoking interaction analyses were also carried out, as in the test dataset. […]

Pipeline specifications

Software tools Tagger, PedCheck, PBAT
Application GWAS
Diseases Pulmonary Disease, Chronic Obstructive
Chemicals Iron, Nicotine