PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-2 (2)
 

Clipboard (0)
None
Journals
Authors
more »
Year of Publication
Document Types
1.  Determinants of airflow obstruction in severe alpha‐1‐antitrypsin deficiency 
Thorax  2007;62(9):806-813.
Background
Severe α1‐antitrypsin (AAT) deficiency is an autosomal recessive genetic condition associated with an increased but variable risk for chronic obstructive pulmonary disease (COPD). A study was undertaken to assess the impact of chronic bronchitis, pneumonia, asthma and sex on the development of COPD in individuals with severe AAT deficiency.
Methods
The AAT Genetic Modifier Study is a multicentre family‐based cohort study designed to study the genetic and epidemiological determinants of COPD in AAT deficiency. 378 individuals (age range 33–80 years), confirmed to be homozygous for the SERPINA1 Z mutation, were included in the analyses. The primary outcomes of interest were a quantitative outcome, forced expiratory volume in 1 s (FEV1) percentage predicted, and a qualitative outcome, severe airflow obstruction (FEV1 <50% predicted).
Results
In multivariate analysis of the overall cohort, cigarette smoking, sex, asthma, chronic bronchitis and pneumonia were risk factors for reduced FEV1 percentage predicted and severe airflow obstruction (p<0.01). Index cases had lower FEV1 values, higher smoking histories and more reports of adult asthma, pneumonia and asthma before age 16 than non‐index cases (p<0.01). Men had lower pre‐ and post‐bronchodilator FEV1 percentage predicted than women (p<0.0001); the lowest FEV1 values were observed in men reporting a history of childhood asthma (26.9%). This trend for more severe obstruction in men remained when index and non‐index groups were examined separately, with men representing the majority of non‐index individuals with airflow obstruction (71%). Chronic bronchitis (OR 3.8, CI 1.8 to 12.0) and a physician's report of asthma (OR 4.2, CI 1.4 to 13.1) were predictors of severe airflow obstruction in multivariate analysis of non‐index men but not women.
Conclusion
In individuals with severe AAT deficiency, sex, asthma, chronic bronchitis and pneumonia are risk factors for severe COPD, in addition to cigarette smoking. These results suggest that, in subjects severely deficient in AAT, men, individuals with symptoms of chronic bronchitis and/or a past diagnosis of asthma or pneumonia may benefit from closer monitoring and potentially earlier treatment.
doi:10.1136/thx.2006.075846
PMCID: PMC2117297  PMID: 17389752
2.  Association of IREB2 and CHRNA3 polymorphisms with airflow obstruction in severe alpha-1 antitrypsin deficiency 
Respiratory Research  2012;13(1):16.
Background
The development of COPD in subjects with alpha-1 antitrypsin (AAT) deficiency is likely to be influenced by modifier genes. Genome-wide association studies and integrative genomics approaches in COPD have demonstrated significant associations with SNPs in the chromosome 15q region that includes CHRNA3 (cholinergic nicotine receptor alpha3) and IREB2 (iron regulatory binding protein 2).
We investigated whether SNPs in the chromosome 15q region would be modifiers for lung function and COPD in AAT deficiency.
Methods
The current analysis included 378 PIZZ subjects in the AAT Genetic Modifiers Study and a replication cohort of 458 subjects from the UK AAT Deficiency National Registry. Nine SNPs in LOC123688, CHRNA3 and IREB2 were selected for genotyping. FEV1 percent of predicted and FEV1/FVC ratio were analyzed as quantitative phenotypes. Family-based association analysis was performed in the AAT Genetic Modifiers Study. In the replication set, general linear models were used for quantitative phenotypes and logistic regression models were used for the presence/absence of emphysema or COPD.
Results
Three SNPs (rs2568494 in IREB2, rs8034191 in LOC123688, and rs1051730 in CHRNA3) were associated with pre-bronchodilator FEV1 percent of predicted in the AAT Genetic Modifiers Study. Two SNPs (rs2568494 and rs1051730) were associated with the post-bronchodilator FEV1 percent of predicted and pre-bronchodilator FEV1/FVC ratio; SNP-by-gender interactions were observed. In the UK National Registry dataset, rs2568494 was significantly associated with emphysema in the male subgroup; significant SNP-by-smoking interactions were observed.
Conclusions
IREB2 and CHRNA3 are potential genetic modifiers of COPD phenotypes in individuals with severe AAT deficiency and may be sex-specific in their impact.
doi:10.1186/1465-9921-13-16
PMCID: PMC3306733  PMID: 22356581
CHRNA3; Chronic obstructive pulmonary disease; Genetic association analysis; Genetic modifiers; IREB2

Results 1-2 (2)