The Effects of Rare <i>SERPINA1</i> Variants on Lung Function and Emphysema in SPIROMICS

Ortega, Victor E.; Li, Xingnan; O’Neal, Wanda K.; Lackey, Lela; Ampleford, Elizabeth; Hawkins, Gregory A.; Grayeski, Philip J.; Laederach, Alain; Barjaktarević, Igor; Barr, R. Graham; Cooper, Christopher B.; Couper, David; Han, Mei Lan K.; Kanner, Richard E.; Kleerup, Eric C.; Martínez, Fernando J.; Paine, Robert; Peters, Stephen P.; Pirozzi, C.S.; Rennard, Stephen I.; Woodruff, Prescott G.; Hoffman, Eric A.; Meyers, Deborah A.; Bleecker, Eugene R.

doi:10.1164/rccm.201904-0769oc

Cited by 47 publications

(37 citation statements)

References 45 publications

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“…xMAP technology has been applied to determine AAT concentration in different samples such as serum, plasma, urine, or sputum. Aside from AATD patients [ 28 ], it has also been used to measure AAT concentration, along with other molecules, as a biomarker of disease severity in ulcerative colitis [ 29 ], long-term recovery of chronic disorder of consciousness [ 30 ], bladder cancer diagnosis signature [ 31 ], or inflammatory profile in chronic obstructive pulmonary disease [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

Methodologies for the Determination of Blood Alpha1 Antitrypsin Levels: A Systematic Review

Ruiz-Duque

Bañuls

Reinoso-Arija

et al. 2021

JCM

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Background: The study of hematic concentrations of alpha1 antitrypsin (AAT) is currently one step in the diagnosis of AAT deficiency. To try to clarify the relevance of the laboratory techniques, we carried out a systematic review of the literature. Methods: Studies evaluating the quantification of AAT in peripheral blood were searched in PubMed in July 2021. The selection criteria included (1) any type of study design that included a quantification of AAT in peripheral blood; (2) studies written in English or Spanish; (3) studies evaluating human beings; and (4) studies involving adults. Results: Out of 207 studies, the most frequently used techniques were nephelometry (43.9%), followed by ELISA (19.8%) and turbidimetry (13.5%). Altogether, 182 (87.9%) cases expressed their results in units of gram, while 16 (7.7%) articles expressed them in units of mole. Only 2.9% articles referred to the standard used, 43.5% articles indicated the commercial kit used, and 36.2% indicated the analyzer used. Conclusions: The technical aspects of these determinations are not always reported in the literature. Journals should be attentive to these technical requirements and ensure that they are included in the works in which AAT is determined in order to ensure a correct interpretation of the study findings.

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Section: Discussionmentioning

confidence: 99%

Methodologies for the Determination of Blood Alpha1 Antitrypsin Levels: A Systematic Review

Ruiz-Duque

Bañuls

Reinoso-Arija

et al. 2021

JCM

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“…Several case–control studies indicated a higher prevalence of the PI*MZ genotype among patients with COPD compared with controls without COPD [ 31 – 33 ]. A recently published analysis of a large cohort of individuals with COPD showed that PI*Z heterozygotes with a significant cigarette smoking history are at an increased risk of COPD compared with ever-smoker PI*MM individuals, have lower lung function, greater airflow obstruction and greater computed tomography (CT)-based quantitative measures of emphysema [ 34 , 35 ]. These reports suggest that PI*MZ patients have a higher susceptibility to smoking-related lung disease.…”

Section: Main Textmentioning

confidence: 99%

Alpha-1 antitrypsin (AAT) augmentation therapy in individuals with the PI*MZ genotype: a pro/con debate on a working hypothesis

Miravitlles

2021

BMC Pulm Med

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Alpha-1 antitrypsin deficiency (AATD) is a significantly under-diagnosed genetic condition caused by reduced levels and/or functionality of alpha-1 antitrypsin (AAT), predisposing individuals to lung, liver or other systemic diseases. The management of individuals with the PI*MZ genotype, characterized by mild or moderate AAT deficiency, is less clear than of those with the most common severe deficiency genotype (PI*ZZ). Recent genetic data suggest that the PI*MZ genotype may be significantly more prevalent than currently thought. The only specific treatment for lung disease associated with severe AATD is the intravenous infusion of AAT augmentation therapy, which has been shown to slow disease progression in PI*ZZ individuals. There is no specific evidence for the clinical benefit of AAT therapy in PI*MZ individuals, and the risk of emphysema development in this group remains controversial. As such, current guidelines do not support the use of AAT augmentation in PI*MZ individuals. Here, we discuss the limited data on the PI*MZ genotype and offer pro and con perspectives on pursuing an AAT-specific therapeutic strategy in PI*MZ individuals with lung disease. Ultimately, further research to demonstrate the safety, risk/benefit balance and efficacy of AAT therapy in PI*MZ individuals is needed.

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“…For decades, the MZ genotype was considered to represent a "carrier" state. Recently however, an interaction between the MZ genotype and smoking has been shown to significantly increase the risk of COPD [5] and the severity of airflow obstruction relative to usual (MM) smokers [6,7]. Consequently, MZ AATD smokers represent a common, high-risk subgroup, with a genetically predetermined course toward greater morbidity.…”

Section: Introductionmentioning

confidence: 99%

Alpha-1 Antitrypsin Deficiency and Tobacco Smoking: Exploring Risk Factors and Smoking Cessation in a Registry Population

Franciosi

Alkhunaizi

Woodsmith

et al. 2021

COPD: Journal of Chronic Obstructive Pulmonary Disease

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The ZZ genotype of alpha-1 antitrypsin deficiency (AATD) is strongly associated with COPD, even in never-smokers. Moderate AATD genotypes (MZ and SZ) have been shown to increase the severity of COPD in smokers. In this comparative study, we examine the association between AATD, genotypes, and smoking cessation. Two hundred and ninety-three Irish people with AATD [MZ (n ¼ 91), SZ (n ¼ 72), and ZZ/rare (n ¼ 130)] completed a custom questionnaire assessing their social and smoking histories. The primary outcomes analyzed were the predictors of ever-smoking and effect of genotype on awareness of AATD and maintained smoking cessation, using logistic regression analyses. Parental smoking exposure was associated with ever-smoking status (OR 1.84 vs. no parental smoking, p ¼ 0.018), higher cumulative tobacco consumption (23.47 vs. 14.87 packyears, p ¼ 0.005) and more quit attempts required to achieve cessation among former-smokers (2.97 vs. 5.60, p ¼ 0.007). Awareness of genotype was 67.7% versus 56.3% versus 33% for ZZ, SZ, and MZ, respectively (p < 0.001). Among ever-smokers, current-smoking was uncommon (2.5% vs. 17% vs. 16% for ZZ, SZ, and MZ, respectively, p ¼ 0.009) with ZZs significantly less likely to be current-smokers (OR 0.15 relative to MZ, p ¼ 0.025). These results suggest that the genetic risk of COPD in AATD families is compounded by transmission of social risk factors (via parental smoking). Increasing severity of genotype is associated with lower current-smoking rates among eversmokers. Whether this is attributable to greater awareness of risk is an area of interest. Achieving a change in smoking habits may also result in positive health behavior in subsequent generations.

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The Effects of Rare SERPINA1 Variants on Lung Function and Emphysema in SPIROMICS

Cited by 47 publications

References 45 publications

Methodologies for the Determination of Blood Alpha1 Antitrypsin Levels: A Systematic Review

Methodologies for the Determination of Blood Alpha1 Antitrypsin Levels: A Systematic Review

Alpha-1 antitrypsin (AAT) augmentation therapy in individuals with the PI*MZ genotype: a pro/con debate on a working hypothesis

Alpha-1 Antitrypsin Deficiency and Tobacco Smoking: Exploring Risk Factors and Smoking Cessation in a Registry Population

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