Obstructive Lung Disease and Trypsin Inhibitors in α<sub>1</sub>-Antitrypsin Deficiency

Ganrot, P. O.; Laurell, C.‐B.; Eriksson, Sten

doi:10.3109/00365516709090627

Cited by 119 publications

(43 citation statements)

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“…In a,ATD PiZ, the ratio is decreased to about 2: 1 in adults and 1:2 in 8-yrold children, indicating a relatively important role of a2M in u,ATD during childhood. The wide a2M range, 230-44070 in healthy children, may also be an endogenous factor explaining the wide clinical variation of lung disease in adult aIATD subjects, although, no significant difference of a2M was found between alATD adults with and without chronic lung disease (6).…”

Section: Discussionmentioning

confidence: 86%

Plasma Protease Inhibitors in α1-Antitrypsin-Deficient Children

Sveger

1985

Pediatr Res

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Section: Discussionmentioning

confidence: 86%

Plasma Protease Inhibitors in α1-Antitrypsin-Deficient Children

Sveger

1985

Pediatr Res

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“…However, the only proven genetic risk factor for COPD is a severe deficiency of a 1 -antitrypsin (11), which is present in only 1-2% of individuals with COPD. Major COPD susceptibility loci have recently been identified on chromosomes 4 (near hedgehog interacting protein [HHIP] and FAM13A) and 15 (in a linkage disequilibrium block including components of the cholinergic nicotinic acetylcholine receptor, CHRNA3/5, and the IREB2 gene) in genome-wide association studies (GWAS) of COPD and related phenotypes (12)(13)(14).…”

mentioning

confidence: 99%

Loci Identified by Genome-wide Association Studies Influence Different Disease-related Phenotypes in Chronic Obstructive Pulmonary Disease

Pillai

Kong²,

Edwards³

et al. 2010

Am J Respir Crit Care Med

128

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Rationale: Genome-wide association studies have shown significant associations between variants near hedgehog interacting protein HHIP, FAM13A, and cholinergic nicotinic acetylcholine receptor CHRNA3/5 with increased risk of chronic obstructive pulmonary disease (COPD) in smokers; however, the disease mechanisms behind these associations are not well understood. Objectives: To identify the association between replicated loci and COPD-related phenotypes in well-characterized patient populations. Methods: The relationship between these three loci and COPDrelated phenotypes was assessed in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-point (ECLIPSE) cohort. The results were validated in the family-based International COPD Genetics Network (ICGN). Measurements and Main Results: The CHRNA3/5 locus was significantly associated with pack-years of smoking (P 5 0.002 and 3 3 10 24 ), emphysema assessed by a radiologist using high-resolution computed tomography (P 5 2 3 10 24 and 4.8 3 10 25 ), and airflow obstruction (P 5 0.004 and 1.8 3 10 25 ) in the ECLIPSE and ICGN populations, respectively. However, variants in the IREB2 gene were only significantly associated with FEV 1 . The HHIP locus was not associated with smoking intensity but was associated with FEV 1 /FVC (P 5 1.9 3 10 24 and 0.004 in the ECLIPSE and ICGN populations). The HHIP locus was also associated with fat-free body mass (P 5 0.007) and with both retrospectively (P 5 0.015) and prospectively (P 5 0.024) collected COPD exacerbations in the ECLIPSE cohort. Single-nucleotide polymorphisms in the FAM13A locus were associated with lung function. Conclusions: The CHRNA3/5 locus was associated with increased smoking intensity and emphysema in individuals with COPD, whereas the HHIP and FAM13A loci were not associated with smoking intensity. The HHIP locus was associated with the systemic components of COPD and with the frequency of COPD exacerbations. FAM13A locus was associated with lung function.Keywords: COPD exacerbations; nicotine addiction; high-resolution CT; genetic association analysis; emphysema Chronic obstructive pulmonary disease (COPD) is a common condition that is intimately linked with cigarette smoking and is predicted to be the third leading cause of mortality and the fifth leading cause of morbidity in the world by the year 2020 (1). COPD is characterized by the presence of airflow limitation resulting from airway inflammation and remodelling or lung parenchymal destruction with emphysema. Although COPD severity is typically determined by spirometric measures (2), there is extensive heterogeneity in the amount of emphysema, degree of functional impairment, and frequency of exacerbations among patients with COPD with the same level of airflow obstruction (3). COPD can be associated with systemic manifestations, such as cachexia, which can effectively result in impaired functional capacity, worsening dyspnea, reduced health-related quality of life, and increased mortality (4).Familial aggregation studies suggest ...

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“…The latter takes the form of cholestatic jaundice in infancy (neonatal hepatitis), childhood cirrhosis and, less often, cirrhosis in adults. In addition, a few cases of hepatocellular (11CC) or cholangiocellular cancer have been described in patients with homozygous (ZZ) or heterozygous (MZ) AAT deficiency (Ganrot et al, 1967;Accepted 29 December 1977 Berg and Eriksson, 1972;Eriksson and Hiagerstrand, 1974;Aagenaes et al, 1974;Lieberman, 1974;Rawlings, et al, 1974;Williams and Fajardo, 1974;Lieberman et al, 1975;Zwi et al, 1975). A characteristic finding in individuals with both homozygous or heterozygous AAT deficiency, in the presence or absence of liver disease, is the accumulation of periodic acid-Schiff (PAS)-positive, diastase-resistant globules in periportal hepatocytes (Sharp, 1971).…”

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confidence: 99%

“…AAT deficiency has been shown to be associated with a variety of diseases, but particularly with chronic obstructive pulmonary disease (Ganrot et al, 1967) and liver disease (Berg and Eriksson, 1972;Feldman et al, 1974;Sharp, 1976). The latter takes the form of cholestatic jaundice in infancy (neonatal hepatitis), childhood cirrhosis and, less often, cirrhosis in adults.…”

mentioning

confidence: 99%