Alpha-1 Carrier Genomics Study

Study Overview
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Brief Summary
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The goal of this study is to better understand why some Alpha-1 genotype MZ (PiMZ) individuals develop chronic obstructive pulmonary disease (COPD) while others do not. This study will examine portions of the Alpha-1 gene that are not routinely tested to determine whether other changes in this gene correlate with development and progression of COPD. Participation involves responding to questionnaires about lung health and history, and performing an at-home finger stick to obtain blood spots using a test kit that is mailed. The blood provided will be used for genetic testing and correlation of results with COPD history. Participants will receive their results and access to genetic counseling at the conclusion of the study.

Detailed Description
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Alpha-1 Antitrypsin Deficiency (AATD, Alpha-1) is the best established genetic risk factor for chronic obstructive pulmonary disease (COPD) and liver disease. Clinical presentation is heterogeneous in most genotypic populations of alpha-1 antitrypsin deficiency (AATD) and genetic variation in the Alpha-1 gene has been incompletely studied. Rare gene alterations that predispose to COPD risks of classic AATD in individuals without a classic homozygous deficiency genotype have not been studied and are important in understanding, testing and treating at-risk populations. Investigators hypothesize that SERPINA1 gene sequencing will find important sequence variations in previously assessed MZ individuals who have COPD compared to age, race, sex, AAT level and smoking status matched MZ individuals who do not have COPD. The Alpha-1 Carrier Genomics study is a pilot study that will enroll up to 150 MZ individuals. COPD+ and COPD- individuals will be matched on age, sex, race and smoking history. Presence and severity of COPD is assessed by a COPD severity score on questionnaires. Participants will be mailed a test kit to obtain and return a blood sample by finger stick for the purpose of SERPINA1 gene sequencing. Gene sequencing will identify, if present, genomic signatures that may correlate with COPD in this cohort. Participants will receive their results and access to genetic counseling at the conclusion of this study.

Official Title
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Alpha-1 Carrier Genomics Study

Conditions
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COPD, Alpha-1 Antitrypsin Deficiency, Emphysema, Smoking

Intervention / Treatment
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* Genetic: Genetic Sequencing


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent PiMZ individuals who fall into the lower quartile of AAT levels. Exclusion Criteria: Age <18 years Known homozygous or compound heterozygous classic severe AATD (e.g. PiSZ, ZZ, Znull)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| MZ heterozygote with symptoms of COPD<br>Individuals who have previously had testing for Alpha-1 antitrypsin deficiency with genotype MZ (PiMZ) results. Individuals in this cohort have symptoms or clinical diagnosis of COPD. | Genetic: Genetic Sequencing<br>* Sequencing of the SERPINA1 gene<br>|
| MZ heterozygote without symptoms of COPD<br>Individuals who have previously had testing for Alpha-1 antitrypsin deficiency with genotype MZ (PiMZ) results. Individuals in this cohort do not have symptoms or clinical diagnosis of COPD. | Genetic: Genetic Sequencing<br>* Sequencing of the SERPINA1 gene<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Abnormal Sequences in SERPINA1 Genes | Additional SERPINA1 variant of known or possible significance detected by next generation sequencing. | End of study NGS Result | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MZ, Alpha-1 antitrypsin deficiency, AATD, Alpha-1, SERPINA1, Carrier, Heterozygote, Smoking, COPD, Emphysema, Sequencing