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author:("gulik, amend")
1.  Identification of FGF7 as a novel susceptibility locus for chronic obstructive pulmonary disease 
Thorax  2011;66(12):1085-1090.
Traditional genome-wide association studies (GWAS) of large cohort of subjects with chronic obstructive pulmonary disease (COPD) have successfully identified novel candidate genes, but several other plausible loci do not meet strict criteria for genome-wide significance after correction for multiple testing.
We hypothesize that by applying unbiased weights derived from unique populations we can identify additional COPD susceptibility loci.
We performed a homozygosity haplotype analysis on a group of subjects with and without COPD to identify regions of conserved homozygosity (RCHH). Weights were constructed based on the frequency of these RCHH in case vs. controls, and used to adjust the P values from a large collaborative GWAS of COPD.
We identified 2,318 regions of conserved homozygosity, of which 576 were significantly (P < .05) overrepresented in cases. After applying the weights constructed from these regions to a collaborative GWAS of COPD, we identified two single nucleotide polymorphisms in a novel gene (FGF7) that gained genome-wide significance by the false discovery rate method. In a follow-up analysis, both SNPs (rs12591300 and rs4480740) were significantly associated with COPD in an independent population (combined P values of 7.9E-07 and 2.8E-06 respectively). In another independent population, increased lung tissue FGF7 expression was associated with worse measures of lung function.
Weights constructed from a homozygosity haplotype analysis of an isolated population successfully identify novel genetic associations from a GWAS on a separate population. This method can be used to identify promising candidate genes that fail to meet strict correction for multiple testing.
PMCID: PMC3348619  PMID: 21921092
2.  Genome-wide association study of smoking behaviors in COPD patients 
Thorax  2011;66(10):894-902.
Cigarette smoking is a major risk factor for COPD and COPD severity. Previous genome-wide association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) associated with the number of cigarettes smoked per day (CPD) and a Dopamine Beta-Hydroxylase (DBH) locus associated with smoking cessation in multiple populations.
To identify SNPs associated with lifetime average and current CPD, age at smoking initiation, and smoking cessation in COPD subjects.
GWAS were conducted in 4 independent cohorts encompassing 3,441 ever-smoking COPD subjects (GOLD stage II or higher). Untyped SNPs were imputed using HapMap (phase II) panel. Results from all cohorts were meta-analyzed.
Several SNPs near the HLA region on chromosome 6p21 and in an intergenic region on chromosome 2q21 showed associations with age at smoking initiation, both with the lowest p=2×10−7. No SNPs were associated with lifetime average CPD, current CPD or smoking cessation with p<10−6. Nominally significant associations with candidate SNPs within alpha-nicotinic acetylcholine receptors 3/5 (CHRNA3/CHRNA5; e.g. p=0.00011 for SNP rs1051730) and Cytochrome P450 2A6 (CYP2A6; e.g. p=2.78×10−5 for a nonsynonymous SNP rs1801272) regions were observed for lifetime average CPD, however only CYP2A6 showed evidence of significant association with current CPD. A candidate SNP (rs3025343) in the DBH was significantly (p=0.015) associated with smoking cessation.
We identified two candidate regions associated with age at smoking initiation in COPD subjects. Associations of CHRNA3/CHRNA5 and CYP2A6 loci with CPD and DBH with smoking cessation are also likely of importance in the smoking behaviors of COPD patients.
PMCID: PMC3302576  PMID: 21685187
Chronic Obstructive Pulmonary Disease (COPD); Genome Wide Association study (GWAS); smoking behaviors; Single Nucleotide Polymorphism (SNP)
3.  Feasible and simple exclusion criteria for pulmonary reference populations 
Thorax  2007;62(9):792-798.
International guidelines recommend that pulmonary reference populations consist of never‐smokers without respiratory diseases or symptoms, but the diseases and symptoms are not clearly specified. The present study aimed to identify simple exclusion criteria for defining pulmonary reference populations.
Based on a random sample from a general population (the parent population), 2358 subjects aged 26–82 years performed spirometric tests. From this sample, subjects were stepwise excluded according to self‐reported obstructive lung diseases, symptoms and smoking history. Four increasingly more healthy respiratory reference populations were formed. Prediction equations for the median and lower limit of normal lung function were derived using quantile regression analysis.
Subjects without self‐reported obstructive lung diseases or the cardinal respiratory symptoms of breathlessness, cough or wheeze (population B), never‐smokers without cardinal symptoms (population C) and never‐smokers without any respiratory symptoms (population D) constituted 50% (n = 1184), 23% (n = 539) and 14% (n = 331) of the parent population (population A), respectively. The largest discrepancy between prediction equations was found between the parent population and the population without cardinal respiratory symptoms (population B) (p<0.05). Minor changes in the reference equations were also seen when excluding ever‐smokers (population C). There was no additional change with exclusion of other respiratory symptoms (population D). Age‐related decline in lung function was steepest in the parent population.
Obstructive lung diseases, smoking history, breathlessness, cough and wheeze are optimal exclusion criteria for a pulmonary reference population. Further validation of the exclusion criteria identified in this study is recommended with identical wording in other and larger multinational populations.
PMCID: PMC2117321  PMID: 17389756

Results 1-3 (3)