SERPINA1 Gene Variants in Individuals from the General Population with Reduced α1-Antitrypsin Concentrations

Abstract

the SAPALDIA Team BACKGROUND: Individuals with severe deficiency in serum ␣ 1 -antitrypsin (AAT) concentrations are at high risk for developing chronic obstructive pulmonary disease (COPD), whereas those carrying the PI*MZ genotype are at slightly increased risk. Testing appropriate subgroups of the population for AAT deficiency (AATD) is therefore an important aspect of COPD prevention and timely treatment. We decided to perform an exhaustive investigation of SERPINA1 gene variants in individuals from the general population with a moderately reduced serum AAT concentration, because such information is currently unavailable.

Polymerization and Oxidation of Alpha-1-Antitrypsin in Pathogenesis of Emphysema

“…Thus, serum levels might be "falsely elevated" and are not reflecting the genotype, especially in moderate A1ATD. This was confirmed in a recent study which found that PiMZ individuals with a higher level of C-reactive protein (CRP, a sensitive marker of inflammation) had higher level of A1AT than those with lower level of CRP (Zorzetto et al, 2008). Also, we should bear in mind that in healthy blood donors only 26% of the variance of circulating A1AT level is explained by known SERPINA1 gene variants (Oakeshott et al, 1985).…”

“…Phenotyping by isoelectric focusing is often used to characterize  1 AT deficiency, but this method may lead to misdiagnosis (e.g., by missing null alleles). Zorzetto et al (Zorzetto et al, 2008) sequenced exons II, III, IV, and V of subjects whose are negative for Z and S alleles, and detected even 7% rare A1ATD alleles. Moreover, Prins et al (Prins et al, 2008) have analyzed patients with A1ATD by sequencing of exons II, III, and V of the SERPINE1 gene and reported that up to 22% of deficiency variants were missed by conventional diagnostic methods.…”

Alpha-1 Antitrypsin Deficiency – A Genetic Risk Factor for COPD

“…(Kok, Willems, and Drenth 2010). A Swiss-Italian study has shown that MZ individuals with a C-reactive protein (CRP) level of > 0.8 g/L had higher mean AAT concentrations than MZ individuals with lower CRP levels, reflecting the acute phase nature of AAT production (Zorzetto et al 2008). The cautionary note in using CRP levels to correct for systemic inflammation and an acute phase response when measuring AAT is that CRP is also liver-derived.…”

The Role of Alpha-1 Antitrypsin in Emphysema

“…Genotyping by real-time PCR and Restriction Fragment-Length Polymorphism PCR (RFLP-PCR) are highly effective, relatively inexpensive and reliable, and as a consequence are now commonly performed. Direct sequencing of coding exons of the gene can also be used as an adjunct in selected cases to clarify genotyping (Zorzetto et al, 2008;Miravitlles et al, 2010).…”