Abstract
Background: Previous studies of vitamin D binding protein (VDBP, also known as group-specific component, Gc, encoded by the GC gene) have implicated two gene variants, GC*2 and GC*1F, as possible contributors with chronic obstructive pulmonary disease (COPD) protection and susceptibility, respectively. The objective of this study was to examine the association of VDBP to different subtypes of COPD.
Study design: The association of the various GC genotypes to the COPD phenotype was examined in Icelandic COPD patients who were followed by pulmonary physicians at the University Hospital of Iceland.
Methods: All patients were genotyped for the known alleles of the GC gene. The single nucleotide polymorphisms (SNPs) were identified by a restriction fragment length polymorphism procedure. Study power was estimated based on allele frequencies of the variants, and risk ratios were calculated from the prevalence of genotypes in the affected group divided by its prevalence in the control population. Statistical analyses were performed using the 2-tailed Fisher’s Exact Test and χ2 test, where appropriate.
Patient group: One hundred and two COPD patients and 183 controls, together with 46 asthma patients and 48 patients with chronic mucous hypersecretion (CMH) were examined.
Main outcome measure and results: The results demonstrate similar allele and genotype frequencies of GC in COPD patients overall and healthy controls. However, there was a higher prevalence of genotypes carrying a GC*1F allele and lower prevalence of genotypes with a GC*2 allele in the CMH patients than in controls. This difference was most notable in the homozygous form: 8.3% vs 1.1% for the GC*1F/*1F, and 0.0% vs 7.6% for the GC*2/*2 genotypes, respectively. When controlled for smoking, only the non-smoking CMH patients demonstrated a significantly altered frequency of the GC*1F/*1F genotype (p = 0.0001). The prevalence of the GC*2/*2 genotype was also significantly lower in patients with bronchial hypersecretion with airflow obstruction compared with the control group (2.9% vs 7.6%). Taken together, these results demonstrate that the GC*1F and GC*2 alleles are associated with sputum hypersecretion in individuals who are at increased risk of developing COPD.
References
Daiger SP, Schanfield MS, Cavalli-Sforza LL. Group-specific component (Gc) proteins bind vitamin D and 25-hydroxyvitamin D. Proc Natl Acad Sci U S A 1975; 72: 2076–80
Schellenberg D, Paré PD, Weir TD, et al. Vitamin D binding protein variants and the risk of COPD. Am J Respir Crit Care Med 1998; 157: 957–61
Yamamoto N, Homma S. Vitamin D3 binding protein (group-specific component) is a precursor for the macrophage-activating signal factor from lysophosphatidylcholine-treated lymphocytes. Proc Natl Acad Sci U S A 1991; 88: 8539–43
Kueppers F, Miller RD, Gordon H, et al. Familial prevalence of chronic obstructive pulmonary disease in a matched pair study. Am J Med 1977; 63: 336–42
Horne SL, Cockcroft DW, Dosman JA. Possible protective effect against chronic obstructive airways disease by the GC2 allele. Hum Hered 1990; 40: 173–6
Ishii T, Keicho N, Teramoto S, et al. Association of Gc-globulin variation with susceptibility to COPD and diffuse panbronchiolitis. Eur Respir J 2001 Nov; 18(5): 753–7
Kauffmann F, Kleisbauer JP, Cambon-De-Mouzon A, et al. Genetic markers in chronic air-flow limitation: a genetic epidemiologic study. Am Rev Respir Dis 1983; 127: 263
Sandford AJ, Chagani T, Weir TD, et al. Susceptibility genes for rapid decline of lung function in the lung health study. Am J Respir Crit Care Med 2001; 163: 469–73
Daiger SP, Miller M, Chakraborty R. Heritability of quantitative variation at the group-specific component (Gc) locus. Am J Hum Genet 1984; 36: 663–76
American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am J Respir Care Med 1995; 152 (5 Pt 2): S77–121
Gulcher JR, Kristjansson K, Gudbjartsson H, et al. Protection of privacy by third-party encryption in genetic research in Iceland. Eur J Hum Genet 2000; 8: 739–42
Barnes PJ. New treatments for chronic obstructive pulmonary disease. Curr Opin Pharmacol 2001; 1: 217–22
Barnes PJ. Future Advances in COPD Therapy. Respiration. 2001; 68: 441–8
National Institutes of Health. Guidelines for the Diagnosis and Management of Asthma: Expert Panel Report 2, July 1997. Washington, DC: US Government Printing Office, 1997. NIH Publication No. 97-4051
American Thoracic Society. Standardization of spirometry, 1994. Update. Am J Respir Crit Care Med 1995; 152: 1107–36
Kamboh MI, Ferrell RE. Ethnic variation in vitamin D-binding protein (GC): a review of isoelectric focusing studies in human populations. Hum Genet 1986; 72: 281–93
Vestbo J, Prescott E, Lange P. Association of chronic mucus hypersecretion with FEV1 decline and chronic obstructive pulmonary disease morbidity. Am J Respir Crit Care Med 1996; 153: 1530–5
Acknowledgements
This study was funded by deCODE Genetics, Inc. There is no conflict of interest that is related to the content of this manuscript. We are most grateful to our patients who volunteered to participate in this study and special thanks to the nursing staff, sequencing core facility staff and to Mike Frigge for his statistical advice and Sif Oscarson and Harpa Karlsdottir for their study co-ordination role.
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Laufs, J., Andrason, H., Sigvaldason, A. et al. Association of Vitamin D Binding Protein Variants with Chronic Mucus Hypersecretion in Iceland. Am J Pharmacogenomics 4, 63–68 (2004). https://doi.org/10.2165/00129785-200404010-00007
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DOI: https://doi.org/10.2165/00129785-200404010-00007