The demographic and clinical characteristics of the NETT participants are displayed in . Over the period of study, COPD exacerbations defined as COPD-related emergency department visits or hospitalizations occurred in 56% of subjects. Detailed characterizations of the epidemiologic predictors of exacerbations in NETT participants have been reported elsewhere.[27
Demographic Characteristics of 389 NETT Subjects*
Cochran-Armitage trend tests for SNPs in EPHX1, TGFB1, GSTP1, and SERPINE2 were not significant. Those genes were not analyzed further. The SFTPB genotype frequencies for study participants are displayed in . Pairwise linkage disequilibrium was determined for the five SFTPB SNPs by r2 (). There was generally low LD between the SFTPB SNPs. The highest r2 was 0.6 between rs211877 and rs2304566.
Genotype Frequencies for SFTPB SNPs in 389 non-Hispanic White COPD Subjects*
Linkage Disequilibrium Map for Five SFTPB SNPs in 389 NETT Subjects
One SNP in surfactant protein B, rs3024791, a promoter polymorphism, was significantly associated with probability of any exacerbation in the unadjusted Cochran-Armitage trend test (p=0.008). Cochran-Armitage trend tests were non-significant for the remaining SFTPB SNPs. (.)
Association Analysis of SFTPB SNPs for Probability of Any COPD Exacerbation
After adjustment for potentially relevant clinical confounders such as age, gender, FEV1, smoking history, medical versus surgical treatment, and follow-up time, having more copies of the minor allele of rs3024791, OR 0.6 [95% CL 0.4, 0.9], p = 0.007 was associated with a reduction in the odds of experiencing COPD exacerbations, independent of the treatment effect.(.)
Multivariable Logistic Regression For Probability of Any Exacerbation*§‡
Enrollment into the NETT occurred between January 1998 and July 2002. Enrollment during the latter years of the study resulted in only 29 months for CMS data to accrue post-randomization. As a sensitivity analysis to account for variable follow-up time, an analysis of claims data was limited to 3.3 years (1 year prior to randomization and 2.3 years after randomization) in the logistic regression models. Seven individuals had < 2.3 years of follow-up time. All seven individuals died after randomization. Their data were not excluded from this analysis. Controlling for relevant covariates in an additive model, the T allele of rs3024791 was significantly associated with a reduction in the odds of COPD exacerbations, OR 0.6 (95% CI 0.4–0.9), p = 0.02.
Of the 389 study subjects in the 8-year period of study, 216 participants (56%) experienced 575 exacerbations resulting in an overall exacerbation rate of 0.29 exacerbation events per person-year. The majority of the cohort experienced ≤ 4 total events (median = 1, interquartile range = 2). Stratified by medical versus surgical treatment, 183 subjects (47%) were treated non-surgically and 206 subjects (53%) underwent LVRS. In the medical group, 110 subjects experienced 307 exacerbations resulting in 0.32 events per person year in the medical arm. In the surgically treated group, 106 subjects experienced 268 exacerbations resulting in an exacerbation frequency of 0.25 events per person-year in the surgical arm. Delayed surgical therapy could artificially affect the exacerbation frequency by reducing the number of exacerbations experienced during the post-operative period. Most individuals, however, underwent LVRS soon after randomization. The median time to LVRS in this exacerbation cohort was 11 days (interquartile range = 6 days). LVRS was performed in these subjects within 20 days (90th percentile).
In the Poisson analyses (), four of five polymorphisms in SFTPB were significantly associated with COPD exacerbation counts.
Poisson Regression of COPD Exacerbation Rates
The models were constructed with additive genetic coding and adjusted for age, gender, lung function, pack-years, and treatment. Inheritance of one or more copies of minor alleles of the following variants: rs2118177, rs2304566, rs1130866, and rs3024791, was associated with a reduction in exacerbation counts. (Illustrated with genotype survival curves for rs3024791, depicting time to onset of exacerbations, in ) The findings were robust with models constructed with exacerbations separated by thirty days, truncating follow-up at four years, or using the entire CMS data collected over eight years.
Time to COPD Exacerbation Onset for 379 NETT Subjects Stratified SFTPB rs3024791 Genotype
For the binary exacerbations phenotype, exacerbations ≥ 1 vs. zero exacerbations, haplotype analysis was performed on SFTPB haplotypes of 5% or greater frequency. The global haplotype score p-value for all five SNPs, based on 1000 simulations, was p = 0.03. The C-G-C-A-A haplotype (rs2118177-rs2304566-rs1130866-rs2077079-rs3024791) had the strongest significance (p = 0.009) and a frequency of 6%. Sliding window haplotype analysis was performed with empirical p-values determined by simulation. The strongest association was observed for the two SNP haplotype (rs2077079-rs3024791), p = 0.006; however haplotypes with three loci (rs1130866-rs2077079-rs3024791), p = 0.01, and four loci (rs2304566-rs1130866-rs2077079-rs3024791), p = 0.01, were also significant. The adjusted global haplotype score for all SNPs included the following covariates: age, gender, lung function, pack-years, and treatment received. After 1000 simulations, the adjusted global haplotype p-value was p = 0.03.