Clinical practice. Alpha1-antitrypsin deficiency

Channing Laboratory and Pulmonary and Critical Care Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, USA.
New England Journal of Medicine (Impact Factor: 55.87). 07/2009; 360(26):2749-57.
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    • "A known genetic risk factor for COPD is severe a 1 -antitrypsin (AAT) deficiency, which is the result of mutations in the SERPINA1 (serpin peptidase inhibitor A1) gene [3] [4]. AAT deficiency accounts for approximately 1% of COPD cases and thus is an insufficient genetic factor to account for the heterogeneity in COPD [4]. The complex genetic component of COPD was elucidated through linkage analysis and familial aggregation studies [5]. "
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    ABSTRACT: Chronic obstructive pulmonary disease (COPD) is a complex disease with both environmental and genetic determinants, the most important of which is cigarette smoking. There is marked heterogeneity in the development of COPD among persons with similar cigarette smoking histories, which is likely partially explained by genetic variation. Genomic approaches such as genomewide association studies and gene expression studies have been used to discover genes and molecular pathways involved in COPD pathogenesis; however, these "first generation" omics studies have limitations. Integrative genomic studies are emerging which can combine genomic datasets to further examine the molecular underpinnings of COPD. Future research in COPD genetics will likely use network-based approaches to integrate multiple genomic data types in order to model the complex molecular interactions involved in COPD pathogenesis. This article reviews the genomic research to date and offers a vision for the future of integrative genomic research in COPD.
    Biochemical and Biophysical Research Communications 07/2014; 452(2). DOI:10.1016/j.bbrc.2014.07.086 · 2.30 Impact Factor
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    • "The main cause in the developed world is smoking tobacco in genetically susceptible individuals, but other factors have also been identified (9). Approximately 1% of COPD is associated with functional α1-antitrypsin deficiency (36), which provides the best model of genetic susceptibility to COPD. Current evidence, including data obtained in genomewide association studies (GWAS), shows that susceptibility is complex and may relate in part to epigenetic phenomena (33). "
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    ABSTRACT: Proteinase activated receptor-1 (PAR-1) plays a key role in mediating the interplay between coagulation and inflammation in response to injury. The aim of this study was to investigate the role of the promoter SNP rs2227744G>A in modulating PAR-1/F2R gene expression in the context of chronic obstructive pulmonary disease (COPD) and COPD exacerbations. The function of the rs2227744G>A SNP was investigated using reporter gene assays. The frequency of the polymorphism in the UK population was assessed by genotyping 8579 healthy individuals from the Whitehall II and ELSA cohorts. The rs2227744G>A SNP was genotyped in a carefully phenotyped cohort of 203 COPD cases and matched controls. The results were further replicated in two different COPD cohorts. The minor allele of the rs2227744G>A polymorphism was found to increase F2R expression by 2.6-fold (p<0.001). The rs2227744G>A SNP was not significantly associated with COPD, or with lung function, in all cohorts. The minor allele of the SNP was found to be associated with protection from frequent exacerbations (p=0.04) in the cohort of COPD patients for which exacerbation frequency was available. Considering exacerbations as a continuous variable, the presence of the minor allele was associated with a significantly lower COPD exacerbation rate (3.03 vs 1.98 exacerbations/year, MWU p=0.04). Taken together these data do not support a role for the rs2227744G>A F2R polymorphism in the development of COPD but suggest a protective role for this polymorphism from frequent exacerbations. Studies in separate cohorts to replicate these findings are warranted.
    AJP Lung Cellular and Molecular Physiology 06/2014; 307(4). DOI:10.1152/ajplung.00128.2014 · 4.08 Impact Factor
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    • "The classical form of ATD is an autosomal co-dominant disorder that affects 1 in 3000 live births in many populations; however, a significant number of homozygotes escape both liver and lung disease. There is also a marked variation in the age of onset and severity of lung disease (Silverman and Sandhaus, 2009). We now know that one environmental modifier, cigarette smoking, markedly increases the severity of lung disease and that other genetic and environmental modifiers are also involved. "
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    ABSTRACT: The classical form of α1-antitrypsin deficiency (ATD) is an autosomal co-dominant disorder that affects ~1 in 3000 live births and is an important genetic cause of lung and liver disease. The protein affected, α1-antitrypsin (AT), is predominantly derived from the liver and has the function of inhibiting neutrophil elastase and several other destructive neutrophil proteinases. The genetic defect is a point mutation that leads to misfolding of the mutant protein, which is referred to as α1-antitrypsin Z (ATZ). Because of its misfolding, ATZ is unable to efficiently traverse the secretory pathway. Accumulation of ATZ in the endoplasmic reticulum of liver cells has a gain-of-function proteotoxic effect on the liver, resulting in fibrosis, cirrhosis and/or hepatocellular carcinoma in some individuals. Moreover, because of reduced secretion, there is a lack of anti-proteinase activity in the lung, which allows neutrophil proteases to destroy the connective tissue matrix and cause chronic obstructive pulmonary disease (COPD) by loss of function. Wide variation in the incidence and severity of liver and lung disease among individuals with ATD has made this disease one of the most challenging of the rare genetic disorders to diagnose and treat. Other than cigarette smoking, which worsens COPD in ATD, genetic and environmental modifiers that determine this phenotypic variability are unknown. A limited number of therapeutic strategies are currently available, and liver transplantation is the only treatment for severe liver disease. Although replacement therapy with purified AT corrects the loss of anti-proteinase function, COPD progresses in a substantial number of individuals with ATD and some undergo lung transplantation. Nevertheless, advances in understanding the variability in clinical phenotype and in developing novel therapeutic concepts is beginning to address the major clinical challenges of this mysterious disorder.
    Disease Models and Mechanisms 04/2014; 7(4):411-9. DOI:10.1242/dmm.014092 · 4.97 Impact Factor
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