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Eur Respir J 2007; 30:810-812
Copyright ©ERS Journals Ltd 2007

Variation in the tumour necrosis factor gene is not associated with susceptibility to COPD

S. Chappell1, L. Daly2, K. Morgan1, T. G. Baranes1, J. Roca3, R. Rabinovich3, A. Millar4, S. C. Donnelly5, V. Keatings6, W. MacNee7, J. Stolk8, P. S. Hiemstra8, M. Miniati9, S. Monti9, C. M. O'Connor5,10 and N. Kalsheker1,10

1 Division of Clinical Chemistry, Molecular Medical Sciences, Institute of Genetics, University Hospital, Queens Medical Centre, University of Nottingham, Nottingham, and, 4 Lung Research Group, Dept of Clinical Science at North Bristol, Southmead Hospital, University of Bristol, Westbury on Trym, Bristol, and, 7 Respiratory Medicine, ELEGI Colt Laboratories, Wilkie Building, University of Edinburgh, Edinburgh, UK. 5 School of Medicine and Medical Science, the Conway Institute, and, 2 School of Public Health and Population Science, University College Dublin, Belfield, Dublin, and, 6 Letterkenny General Hospital, Letterkenny, Donegal, Ireland. and, 3 Pulmonary Dept, Hospital Clinic, Hospital Clínico y Provincial de Barcelona, Villarroel, Barcelona, Spain. 8 Dept of Pulmonology (C3-P), Leiden University Medical Center, Leiden, The Netherlands. 9 CNR Institute of Clinical Physiology, Pisa, Italy. 10 Joint senior authors.

To the Editors:

In a recent issue of the European Respiratory Journal, Tanaka et al. 1 studied polymorphisms in the tumour necrosis factor (TNF) and lymphotoxin A genes with respect to their effect on lung function of smokers, and failed to find any association with chronic obstructive pulmonary disease (COPD) phenotypes. Tanaka et al. 1 acknowledge that their work is not a true case–control study, but that it would be better described as an investigation of genetic contribution to disease severity. There have been several studies of variation in TNF with respect to susceptibility to COPD, although many of these have used relatively small sample sizes and are therefore underpowered, and so are likely to lead to results that cannot be replicated.

As part of a European Union collaborative project, we have studied polymorphisms within the TNF gene in a large collection of well-characterised Caucasian COPD patients (n = 1,018) and control subjects (n = 911). COPD cases and control subjects were recruited from six European centres, as previously reported 2. The characteristics of each group are summarised as follows, with data expressed as mean±SD, where appropriate. Controls: 63.5% male; age 60.8±8.9 yrs; smoking history 38.6±17.4 pack-yrs; forced expiratory volume in one second (FEV1) 95.3±10.9% predicted; FEV1/forced vital capacity (FVC) 77.9±4.9%. COPD cases: 69.6% male; age 65.8±8.2 yrs; smoking history 48.9±23.6 pack-yrs; FEV1 43.0±15.3% pred; FEV1/FVC 47.5±12.2%.

Six single nucleotide polymorphisms (SNPs) in TNF (table 1Go) were genotyped using Taqman® probes (Geneservice Ltd, Babraham, UK). Primer and probe sequences are available on request. As quality control measures for the genotyping, 2% of samples of known genotype were included and 10% of samples were present in duplicate to check for concordance. All SNPs were in Hardy–Weinberg equilibrium.


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  		Table 1— Frequency of single nucleotide polymorphisms(SNPs) genotyped in the tumour necrosis factor gene#

 
The association of single SNPs with COPD was carried out using a Chi-squared analysis; none of the SNPs showed a significant difference in genotype frequency between cases and controls (p≥0.331). Linear regression analysis in cases and controls was used to identify any possible effect of TNF genotype on FEV1 (with age, smoking history and sex as covariates). Using a stringent cut-off, this also failed to find any significant effect, with the lowest p-value being obtained for rs1800628 in controls only p = 0.010. Allowing for multiple testing, this is unlikely to be a true association.

A case–control analysis of TNF haplotypes was carried out according to 3. Haplotypes of the TNF SNPs are shown in table 2Go. This analysis identified a total of 10 haplotypes, seven of which were present at a frequency >2%. There was no significant difference in the frequency of these haplotypes between COPD cases and controls (global score statistic = 2.024, 7 degrees of freedom; p = 0.959). Similarly, using the omnibus test performed over all haplotypes in the SAS procedure PROC HAPLOTYPE [4], none of the possible subsets of the six SNPs showed a significant relationship with COPD.


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  		Table 2— Haplotypes of tumour necrosis factor single nucleotide polymorphisms and frequency in cases and controls

 
In this large case–control study using well-characterised COPD patients and controls, we failed to find any association of the TNF polymorphisms with the development of COPD. This is in agreement with other smaller studies in Caucasian populations 5–8, although many studies have only considered the -308 SNP. One study, using 169 Caucasian COPD patients and 358 controls, showed an increase of the 489_GA genotype in the COPD patients with an associated odds ratio of 1.9 9; however, this is not replicated in the current study, suggesting that it may have been a false-positive result.

For allele frequencies ranging 0.05–0.20 (using a dominant model and {alpha} = 0.01), the current study has >80% power to detect minimum effect sizes of 1.4–1.65. The fact that we see no association with any of the tumour necrosis factor single nucleotide polymorphisms or haplotypes makes it highly unlikely that polymorphisms in this gene play a major role in the susceptibility to chronic obstructive pulmonary disease.

REFERENCES

  1. Tanaka G, Sandford AJ, Burkett K, et al. Tumour necrosis factor and lymphotoxin A polymorphisms and lung function in smokers. Eur Respir J 2007;29:34–41.[Abstract/Free Full Text]
  2. Chappell S, Daly L, Morgan K, et al. Cryptic haplotypes of SERPINA1 confer susceptibility to chronic obstructive pulmonary disease. Hum Mutat 2006;27:103–109.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  3. Sinnwell JP, Schaid DJ, Yu Z. Statistical analysis of haplotypes. Version 1.2.2.. http://cran.r-project.org/src/contrib/Descriptions/haplo.stats.html Date last update: June 2007
  4. SAS/Genetics User's Guide. Release 8.2. Cary, SAS Institute Inc., 2002.
  5. Hersh CP, DeMeo DL, Lange C, et al. Attempted replication of reported chronic obstructive pulmonary disease candidate gene associations. Am J Respir Cell Mol Biol 2005;33:71–78.[Abstract/Free Full Text]
  6. Higham MA, Pride NB, Alikhan A, Morrell NW. Tumour necrosis factor-{alpha} gene promoter polymorphism in chronic obstructive pulmonary disease. Eur Respir J 2000;15:281–284.[Abstract]
  7. Patuzzo C, Gilè LS, Zorzetto M, et al. Tumor necrosis factor gene complex in COPD and disseminated bronchiectasis. Chest 2000;117:1353–1358.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  8. Ruse CE, Hill MC, Tobin M, et al. Tumour necrosis factor gene complex polymorphisms in chronic obstructive pulmonary disease. Respir Med 2007;101:340–344.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  9. Küçükaycan M, Van Krugten M, Pennings HJ, et al. Tumor necrosis factor-{alpha} +489G/A gene polymorphism is associated with chronic obstructive pulmonary disease. Respir Res 2002;3:29[CrossRef][Medline] [Order article via Infotrieve]



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