Transcript A Genome-Wide Association Study in Chronic Obstructive Pulmonary Disease (COPD): Identification of Two Major Susceptibility Loci By: Sreekumar G.

A Genome-Wide Association Study in Chronic
Obstructive Pulmonary Disease (COPD):
Identification of Two Major Susceptibility Loci
By: Sreekumar G. Pillai, Dongliang Ge
,et al.
Presented By: Erin Condo
Introduction
• By 2020, Chronic Obstructive Pulmonary
Disease (COPD) is expected to be the 3rd
leading cause worldwide of mortality.
• 80% of people diagnosed with COPD is caused
from smoking
What is COPD?
• COPD is a lung disease characterized by
chronic obstruction of lung airflow that
interferes with normal breathing
The subtypes of COPD
• COPD has 3 subtypes.
1. Emphysema- a condition in which the alveoli in the lungs
are destroyed
2.
Chronic Bronchitis- inflammation of the bronchioles and
excess mucus production
3.
Chronic Asthma- chronic inflammation in the airways
Key Terms;
1.
Single Nucleotide Polymorphisms (SNPs): a DNA sequence variation
occurring when a nucleotide or base pair in the genome differs between
members of a species.
2.
Antitrypsin- a protein produced in the liver, that travels through the
bloodstream. Protects the body’s organs from harmful effects of other
proteins. The lungs are the main organ the protein protects.
Key Terms
1.
Forced Expiratory Volume (FEV)- the amount a person is able to exhale
in the first second of exhalation
2.
Forced Vital Capacity (FVC)-The greatest amount of air which can be
forcibly exhaled from the lungs after taking the deepest breath possible.
3.
FEV1/FVC- a ratio used in the diagnosis of COPD, represents the
amount of air possibly exhaled from the lungs.
Key Terms
1.
2.
Spirometer- instrument used in measuring air capacity of
the lungs
Alplha1-Antitrypsin Deficiency (a1-atd)- severe deficiency
of the protein antitrypsin.
3. Hedgehog interacting protein (HHIP) locus- a gene that
determines a person’s susceptibility of developing COPD.
Key Terms
1. Familial aggregation- Occurrence of a trait in
multiple members of a family than can be
accounted for by chance.
2. Cohort- a group of subjects with a common
defining characteristic. (COPD)
Key Terms
1. Polygenic- multiple genes play a factor
2. Genotyping- the genetic make-up of an organism
3.
Genome-Wide Association (GWA)- a study that examines
common variants in different individuals to see if a variant is
associated with a trait.
4.
Familial aggregation- Occurrence of a trait in multiple
members of a family than can be accounted for by chance.
Key Terms
•
BEOCOPD- Boston Early-Onset COPD, A study that examines
the genetics in COPD.
• NETT- National Emphysema Treatment Trial
•
NAS- Normative Aging Study
• ICGN- International COPD Genetics Network
Review of Literature
•
Lebowitz MD, Knudson RJ, Burrows B, Knudson RJ, Burrows B, et al. (1989) Family
aggregation of pulmonary function measurements. American Review of Respiratory Disease
129:8-11
 Familial aggregation, or replication of a gene in more than one family
member, studies suggest a strong genetic component to the risk of
developing airflow obstruction, or COPD.
Review of Literature
•
Silverman EK, Chapman HA, Drazen JM, Weiss ST, Rosner B, et al. (1998) Genetic
epidemiology of severe, early-onset chronic obstructive pulmonary disease. Risk to relatives
for airflow obstruction and chronic bronchitis. Am J Respir Crit Care Med 157: 1770-1778
 If a subject has developed COPD, there is a chance that their relatives(children
mainly) now have a higher risk to developing COPD due to genetics of a person's
susceptibility of developing COPD.
Review of Literature
•
McCloskey SC, Patel BD, Hinchliffe SJ, Reid ED, Wareham NJ, et al. (2001)
Siblings of patients With Severe Chronic Obstructive Pulmonary Disease
Have a Significant Risk of Airflow Obstruction. American Journal of
Respiratory and Critical Care Medicine 164: 1419-1424
 Siblings are likely to carry some of the same traits, therefore if the
susceptibility of developing airflow obstruction or COPD is genetic in one it
is likely to be genetic in the other.
Review of Literature
•
Ganrot PO, Laurell CB, Eriksson S (1967) Obstructive lung disease and trypsin
inhibitors in alpha-1-antitrypsin deficiency. Scand J Clin Lab Invest 19: 205-208
 a1-atd and the HHIP locus have been replicated numerous amounts of times, that
they are considered statistically significant. In multiple studies.
Hypothesis
• If a1-atd and the HHIP locus are genetic then
they are linked with the susceptibility of
developing COPD
Methods and Materials
• Subjects from different studies such as; GWA study, BEOCOPD, NETT, NAS,
and ICGN all had particapant take place in this
• BEOCOPD subjects were used as an additional family-based replication
cohort.
• Cohort of 389 non-Hispanic white COPD cases from NETT and 472 from
NAS
• 823 COPD cases and 810 controls were present from GWAs.
– Both cases and controls from this group have to have a minimum of
2.5 pack years of smoking.
Methods and Materials
• 1891 Caucasian individuals from ICGN from 606
pedigrees were used as the primary replication
population.
– siblings and available parents were recruited
•
Spirometers were used to measure FEV1/FVC
post bronchodilator usage.
Methods and Materials
•
•
To estimate allele frequencies in the children involved, all
participants provided a written informed consent.
most subjects were genotyped
– They are looking for a genetic variation in the SNPs among the
subjects
– they used a logistic regression model to perform single-marker
genotype trend tests for certain SNPs that replicated.
– also, genotyping in the NETT/NAS and BEOCOPD studies was
performed using TaqMan assays
Results
• Most of the alleles showed inconsistency from the ICGN
population
•
However, at the HHIP locus on chromosome 4, two SNPs
showed continuous replication across the 3 different cohorts
making it significant according to p values.
Results
• A1-atd was proven to be a genetic risk factor to the
development of COPD
• Other genes were found significant in some studies but not
all
– The a-nicotinic acetyl-choline receptor showed replication in the BEOCOPD
study but was not found significant in the other studies
•
The data showed that according to the p-values the 2 genes
were the only two that replication continuously throughout all
of the cohorts
Discussion
• The data from this study clarified that a1-atd is a proven
genetic risk factor to the development of COPD
• The HHIP locus replicated continuously so it eliminated the
null hypothesis but does not yet full prove the hypothesis
however it is considered statistically significant in all 3
cohorts.
Conclusion
• The two genes, A1-ATD and HHIP locus were
found to be significant in replication and are
linked to the susceptibility of a person
developing COPD.
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Questions?