Background
Alpha-1 antitrypsin (AAT) deficiency is an autosomal-codominant disorder, caused by mutations in the SERPINA1 gene on chromosome 14. Individuals affected by the most common mutations, SZ and ZZ, have serum AAT concentrations of 25% and 15% of normal levels, and present a higher risk of emphysema. Mutations causing total absence of serum AAT (Null mutations) were suggested to be associated with very early onset emphysema but their clinical phenotype is poorly known.
Hypothesis
Absence of AAT in Null mutations results in more severe emphysema as compared to ZZ and SZ.
Methods
We genotyped all known Dutch subjects (n=12) with absent serum AAT, and compared their lung function values (FEV1 and KCO) with those of individuals with ZZ and SZ genotype, matched for age and smoking history.
Results
All subjects with absent serum AAT presented homozygous Null mutations. In three subjects, a new mutation in exon 2 of the SERPINA1 gene was found. Subjects with Null mutations showed significantly lower lung function values than SZ and ZZ individuals (p=0.000 and 0.001 for FEV1 and KCO, respectively). In all groups, there was a positive correlation between serum AAT and lung function values (p=0.025 and 0.014 for FEV1 and KCO, respectively).
Conclusions
Serum levels of AAT are correlated with the severity of pulmonary phenotype. Subjects with Null mutations should be considered a subgroup at particularly high risk of emphysema within AAT deficiency (AATD). Early detection of carriers of this genotype would be important for preventive and therapeutic interventions.
Laura Fregonesea, Jan Stolka, Rune R. Frantsb and Barbera Veldhuisen
ARTICLE
Friday
Alpha-1 antitrypsin (A1AT) is a serine anti-protease produced chiefly by the liver. A1AT deficiency is a genetic disorder characterized by serum level
Summary
alpha-1 antitrypsin (A1AT) is a serine anti-protease produced chiefly by the liver. A1AT deficiency is a genetic disorder characterized by serum levels of less than 11 μmol/L and is associated with liver and lung manifestations. The liver disease, which occurs in up to 15% of A1AT-deficient individuals, is a result of toxic gain-of-function mutations in the A1AT gene, which cause the A1AT protein to fold aberrantly and accumulate in the endoplasmic reticulum of hepatocytes. The lung disease is associated with loss-of-function, specifically decreased anti-protease protection on the airway epithelial surface. The so-called ‘Z’ mutation in A1AT deficiency encodes a glutamic acid-to-lysine substitution at position 342 in A1AT and is the most common A1AT allele associated with disease. Here we review the current understanding of the molecular pathogenesis of A1AT deficiency and the best clinical management protocols.
C. M. Greene1 , S. D. W. Miller1, T. Carroll1, C. McLean1, M. O’Mahony1, M. W. Lawless1, 2, S. J. O’Neill1, C. C. Taggart1, 3 and N. G. McElvaney1
alpha-1 antitrypsin (A1AT) is a serine anti-protease produced chiefly by the liver. A1AT deficiency is a genetic disorder characterized by serum levels of less than 11 μmol/L and is associated with liver and lung manifestations. The liver disease, which occurs in up to 15% of A1AT-deficient individuals, is a result of toxic gain-of-function mutations in the A1AT gene, which cause the A1AT protein to fold aberrantly and accumulate in the endoplasmic reticulum of hepatocytes. The lung disease is associated with loss-of-function, specifically decreased anti-protease protection on the airway epithelial surface. The so-called ‘Z’ mutation in A1AT deficiency encodes a glutamic acid-to-lysine substitution at position 342 in A1AT and is the most common A1AT allele associated with disease. Here we review the current understanding of the molecular pathogenesis of A1AT deficiency and the best clinical management protocols.
C. M. Greene1 , S. D. W. Miller1, T. Carroll1, C. McLean1, M. O’Mahony1, M. W. Lawless1, 2, S. J. O’Neill1, C. C. Taggart1, 3 and N. G. McElvaney1
Tuesday
Alpha1-Antitrypsin Deficiency Associated with Increased Risk of Lung Cancer
The disorder, alpha1-antitrypsin deficiency (á1ATD), is one of the most common genetic conditions affecting the U.S. population and especially those of European descent, according to background information in the article. Individuals with two copies of the associated genetic mutation often develop emphysema at an early age. However, á1ATD carriers-those with only one copy of the mutated gene-do not normally have severe diseases related to á1ATD and may not be aware of their status. However, they may be more vulnerable to cancer-causing tobacco smoke than non-carriers.
Ping Yang, M.D., Ph.D., and colleagues at the Mayo Clinic, Rochester, Minn., tested for á1ATD carrier status in 1,443 patients with lung cancer. In addition, 797 community members without lung cancer and 902 siblings of lung cancer patients were tested as controls. Information was gathered about all participants' smoking history, demographic characteristics and family history of cancer.
A total of 13.4 percent of the lung cancer patients and 7.8 percent of unrelated controls were á1ATD carriers. When patients with lung cancer were compared to non-related controls, á1ATD carriers had a 70 percent higher risk of developing lung cancer than non-carriers. Comparing patients with lung cancer to their cancer-free siblings, á1ATD carriers had twice the risk of developing lung cancer. The researchers estimated that á1ATD carrier status may account for 11 percent to 12 percent of the patients with lung cancer enrolled in the study.
Among those who had never smoked, á1ATD carrier status was associated with a 2.2-fold higher risk of lung cancer, with a 2-fold increased risk among light smokers and a 2.3-fold increased risk among moderate to heavy smokers. "Patients with a family history of lung cancer or other cancers in their first-degree relatives had a similar á1ATD carrier rate to those without such a family history, all significantly higher than the controls," the authors write. "This finding suggests that increased lung cancer risk among á1ATD carriers is independent of a family history of cancer."
"In summary, our findings demonstrate a paradigm in lung cancer etiology research and risk assessment that incorporates clinical and genetic markers for lung damage into a gene-environment interaction," they conclude. "This knowledge may prove to be useful in further understanding the pathologic mechanisms of lung cancer development and in refining lung cancer risk assessment."
Ping Yang, M.D., Ph.D., and colleagues at the Mayo Clinic, Rochester, Minn., tested for á1ATD carrier status in 1,443 patients with lung cancer. In addition, 797 community members without lung cancer and 902 siblings of lung cancer patients were tested as controls. Information was gathered about all participants' smoking history, demographic characteristics and family history of cancer.
A total of 13.4 percent of the lung cancer patients and 7.8 percent of unrelated controls were á1ATD carriers. When patients with lung cancer were compared to non-related controls, á1ATD carriers had a 70 percent higher risk of developing lung cancer than non-carriers. Comparing patients with lung cancer to their cancer-free siblings, á1ATD carriers had twice the risk of developing lung cancer. The researchers estimated that á1ATD carrier status may account for 11 percent to 12 percent of the patients with lung cancer enrolled in the study.
Among those who had never smoked, á1ATD carrier status was associated with a 2.2-fold higher risk of lung cancer, with a 2-fold increased risk among light smokers and a 2.3-fold increased risk among moderate to heavy smokers. "Patients with a family history of lung cancer or other cancers in their first-degree relatives had a similar á1ATD carrier rate to those without such a family history, all significantly higher than the controls," the authors write. "This finding suggests that increased lung cancer risk among á1ATD carriers is independent of a family history of cancer."
"In summary, our findings demonstrate a paradigm in lung cancer etiology research and risk assessment that incorporates clinical and genetic markers for lung damage into a gene-environment interaction," they conclude. "This knowledge may prove to be useful in further understanding the pathologic mechanisms of lung cancer development and in refining lung cancer risk assessment."
Alpha-1 Antitrypsin Null Mutations and Severity of Emphysema
Background
Alpha-1 antitrypsin(AAT) deficiency is an autosomal-codominant disorder, caused by mutations in the SERPINA1 gene on chromosome 14. Individuals affected by the most common mutations, SZ and ZZ, have serum AAT concentrations of 25% and 15% of normal levels, and present a higher risk of emphysema. Mutations causing total absence of serum AAT (Null mutations) were suggested to be associated with very early onset emphysema but their clinical phenotype is poorly known.
Hypothesis
Absence of AAT in Null mutations results in more severe emphysema as compared to ZZ and SZ.
Methods
We genotyped all known Dutch subjects (n=12) with absent serum AAT, and compared their lung function values (FEV1 and KCO) with those of individuals with ZZ and SZ genotype, matched for age and smoking history.
Results
All subjects with absent serum AAT presented homozygous Null mutations. In three subjects, a new mutation in exon 2 of the SERPINA1 gene was found. Subjects with Null mutations showed significantly lower lung function values than SZ and ZZ individuals (p=0.000 and 0.001 for FEV1 and KCO, respectively). In all groups, there was a positive correlation between serum AAT and lung function values (p=0.025 and 0.014 for FEV1 and KCO, respectively).
Conclusions
Serum levels of AAT are correlated with the severity of pulmonary phenotype. Subjects with Null mutations should be considered a subgroup at particularly high risk of emphysema within AAT deficiency (AATD). Early detection of carriers of this genotype would be important for preventive and therapeutic interventions.
Laura Fregonesea, Jan Stolka, Rune R. Frantsb and Barbera Veldhuisen
Alpha-1 antitrypsin(AAT) deficiency is an autosomal-codominant disorder, caused by mutations in the SERPINA1 gene on chromosome 14. Individuals affected by the most common mutations, SZ and ZZ, have serum AAT concentrations of 25% and 15% of normal levels, and present a higher risk of emphysema. Mutations causing total absence of serum AAT (Null mutations) were suggested to be associated with very early onset emphysema but their clinical phenotype is poorly known.
Hypothesis
Absence of AAT in Null mutations results in more severe emphysema as compared to ZZ and SZ.
Methods
We genotyped all known Dutch subjects (n=12) with absent serum AAT, and compared their lung function values (FEV1 and KCO) with those of individuals with ZZ and SZ genotype, matched for age and smoking history.
Results
All subjects with absent serum AAT presented homozygous Null mutations. In three subjects, a new mutation in exon 2 of the SERPINA1 gene was found. Subjects with Null mutations showed significantly lower lung function values than SZ and ZZ individuals (p=0.000 and 0.001 for FEV1 and KCO, respectively). In all groups, there was a positive correlation between serum AAT and lung function values (p=0.025 and 0.014 for FEV1 and KCO, respectively).
Conclusions
Serum levels of AAT are correlated with the severity of pulmonary phenotype. Subjects with Null mutations should be considered a subgroup at particularly high risk of emphysema within AAT deficiency (AATD). Early detection of carriers of this genotype would be important for preventive and therapeutic interventions.
Laura Fregonesea, Jan Stolka, Rune R. Frantsb and Barbera Veldhuisen
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