Loci identified by genome-wide association studies influence different disease-related phenotypes in chronic obstructive pulmonary disease.
BACKGROUND
Genome-wide association studies have shown significant associations between variants near hedgehog interacting protein HHIP, FAM13A, and cholinergic nicotinic acetylcholine receptor CHRNA3/5 with increased risk of chronic obstructive pulmonary disease (COPD) in smokers; however, the disease mechanisms behind these associations are not well understood.


OBJECTIVE
To identify the association between replicated loci and COPD-related phenotypes in well-characterized patient populations.


METHODS
The relationship between these three loci and COPD-related phenotypes was assessed in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-point (ECLIPSE) cohort. The results were validated in the family-based International COPD Genetics Network (ICGN).


RESULTS
The CHRNA3/5 locus was significantly associated with pack-years of smoking (P = 0.002 and 3 × 10⁻⁴), emphysema assessed by a radiologist using high-resolution computed tomography (P = 2 × 10⁻⁴ and 4.8 × 10⁻⁵), and airflow obstruction (P = 0.004 and 1.8 × 10⁻⁵) in the ECLIPSE and ICGN populations, respectively. However, variants in the IREB2 gene were only significantly associated with FEV₁. The HHIP locus was not associated with smoking intensity but was associated with FEV₁/FVC (P = 1.9 × 10⁻⁴ and 0.004 in the ECLIPSE and ICGN populations). The HHIP locus was also associated with fat-free body mass (P = 0.007) and with both retrospectively (P = 0.015) and prospectively (P = 0.024) collected COPD exacerbations in the ECLIPSE cohort. Single-nucleotide polymorphisms in the FAM13A locus were associated with lung function.


CONCLUSIONS
The CHRNA3/5 locus was associated with increased smoking intensity and emphysema in individuals with COPD, whereas the HHIP and FAM13A loci were not associated with smoking intensity. The HHIP locus was associated with the systemic components of COPD and with the frequency of COPD exacerbations. FAM13A locus was associated with lung function.
Pillai
Sreekumar G
SG
GlaxoSmithKline, Research Triangle Park, North Carolina, USA. pillaisreekumar@yahoo.com
Kong
Xiangyang
X
Edwards
Lisa D
LD
Cho
Michael H
MH
Anderson
Wayne H
WH
Coxson
Harvey O
HO
Lomas
David A
DA
Silverman
Edwin K
EK
D002352:Carrier Proteins / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D005540:Forced Expiratory Flow Rates; D056426:Genetic Loci; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D035942:Iron Regulatory Protein 2 / Q000235:genetics*; D008297:Male; D013058:Mass Spectrometry; D008562:Membrane Glycoproteins / Q000235:genetics*; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010641:Phenotype; D011379:Prognosis; D011446:Prospective Studies; D029424:Pulmonary Disease, Chronic Obstructive / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D011978:Receptors, Nicotinic / Q000235:genetics*; D012907:Smoking / Q000009:adverse effects; D014057:Tomography, X-Ray Computed
D002352:Carrier Proteins; D035942:Iron Regulatory Protein 2; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D011978:Receptors, Nicotinic; C447158:CHRNA5 protein, human; C117596:HHIP protein, human