Alpha-1 Antitrypsin Deficiency, Emphysema, COPD, Smoking
Conditions
Keywords
Alpha-1 antitrypsin deficiency, AATD, Alpha-1, SERPINA1, MZ, Carrier, Heterozygote, Smoking, COPD, Emphysema, Sequencing
Brief summary
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
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.
Interventions
GENETICGenetic Sequencing
Sequencing of the SERPINA1 gene
Sponsors
CSL Behring
Medical University of South Carolina
Study design
Observational model
CASE_CONTROL
Time perspective
CROSS_SECTIONAL
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Signed informed consent 2. PiMZ individuals who fall into the lower quartile of AAT levels.
Exclusion criteria
1. Age \<18 years 2. Known homozygous or compound heterozygous classic severe AATD (e.g. PiSZ, ZZ, Znull)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Abnormal Sequences in SERPINA1 Genes | End of study NGS Result | Additional SERPINA1 variant of known or possible significance detected by next generation sequencing. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| MZ Heterozygote With Symptoms of COPD 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 Sequencing: Sequencing of the SERPINA1 gene | 76 |
| MZ Heterozygote Without Symptoms of COPD 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 Sequencing: Sequencing of the SERPINA1 gene | 41 |
| Total | 117 |
Baseline characteristics
| Characteristic | MZ Heterozygote Without Symptoms of COPD | Total | MZ Heterozygote With Symptoms of COPD |
|---|---|---|---|
| Age, Continuous Age | 52.8 years | 52 years | 51.7 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 34 Participants | 102 Participants | 68 Participants |
| Sex: Female, Male Female | 28 Participants | 78 Participants | 50 Participants |
| Sex: Female, Male Male | 6 Participants | 25 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 76 | 0 / 41 |
| other Total, other adverse events | 0 / 76 | 0 / 41 |
| serious Total, serious adverse events | 0 / 76 | 0 / 41 |
Outcome results
Primary
Number of Participants With Abnormal Sequences in SERPINA1 Genes
Additional SERPINA1 variant of known or possible significance detected by next generation sequencing.
Time frame: End of study NGS Result
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MZ Heterozygote With Symptoms of COPD | Number of Participants With Abnormal Sequences in SERPINA1 Genes | 6 participants |
| MZ Heterozygote Without Symptoms of COPD | Number of Participants With Abnormal Sequences in SERPINA1 Genes | 0 participants |
Comparison: The MUSC Bioinformatics Core analyzed group genomic data for variant association with COPD severity score, including single variant association or type of variant association with symptoms. Descriptive statistical analysis was performed using statistical package SAS 9.4 for Windows (SAS Institute Inc., Cary, NC, USA).p-value: 0.054Wilcoxon (Mann-Whitney)