Skip to main content
SpringerLink
Log in

SLC11A1 Polymorphisms Are Associated with the Risk of Chronic Obstructive Pulmonary Disease in a Korean Population

  • Published:
Biochemical Genetics Aims and scope Submit manuscript

Abstract

The solute carrier family 11 member 1 (SLC11A1) protein plays important roles in macrophage activation and displays pleiotropic effects on various macrophage functions, including the regulation of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and oxidative burst. Considering the important roles of macrophage in the pathogenesis of chronic obstructive pulmonary disease (COPD), we hypothesized that the SLC11A1 gene may act as a low-penetrance susceptibility gene for COPD. To test this hypothesis, we first examined the frequencies of 12 candidate polymorphisms in the SLC11A1 gene in 27 healthy Korean individuals, and then genotyped 3 haplotype-tagging polymorphisms [IVS4 + 14G > C (rs3731865), D543 N (rs17235409), and *86A > G (rs1059823)] in 83 COPD patients and 203 healthy controls. Individuals with at least one variant allele of the D543 N and *86A > G polymorphisms were at a significantly increased risk for COPD compared with carriers with each homozygous wild-type allele [adjusted odds ratio (OR) = 2.23, 95% confidence interval (CI) = 1.24–4.02, P = 0.007; and adjusted OR = 1.92, 95% CI = 1.10–3.35, P = 0.022, respectively]. Consistent with the findings of the genotyping analysis, the 122 haplotype carrying both the 543 N and *86G alleles was associated with a significantly increased risk for COPD compared with the 111 haplotype with the 542D and *86A alleles (adjusted OR = 2.05, 95% CI = 1.19–3.51, P = 0.009 and Bonferroni corrected P = 0.027). These findings suggest that the SLC11A1 polymorphisms could be used as markers for genetic susceptibility to COPD. However, further studies with large numbers of subjects are needed to confirm our findings.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Barton CH, Whitehead SH, Blackwell JM (1995) Nramp transfection transfers Ity/Lsh/Bcg-related pleiotropic effects on macrophage activation: influence on oxidative burst and nitric oxide pathways. Mol Med 1:267

    PubMed  CAS  Google Scholar 

  • Bascom R (1991) Differential susceptibility to tobacco smoke: possible mechanisms. Pharmacogenetics 1:102

    Article  PubMed  CAS  Google Scholar 

  • Bellamy R, Ruwende C, Corrah T, McAdam KP, Whittle HC, Hill AV (1998) Variations in the Nramp1 gene and susceptibility to tuberculosis in West Africans. N Engl J Med 338:640

    Article  PubMed  CAS  Google Scholar 

  • Blackwell JM, Barton CH, White JK, Searle S, Baker AM, Williams H, Shaw MA (1995) Genomic organization and sequence of the human NRAMP gene: identification and mapping of a promoter region polymorphism. Mol Med 1:194

    PubMed  CAS  Google Scholar 

  • Blackwell JM, Searle S, Goswami T, Miller EN (2000) Understanding the multiple functions of Nramp1. Microbes Infect 2:317

    Article  PubMed  CAS  Google Scholar 

  • Cellier M, Govoni G, Vidal S (1994) Human natural resistance associated macrophage protein: cDNA cloning, chromosomal mapping, genomic organization, and tissue specific expression. J Exp Med 180:1741

    Article  PubMed  CAS  Google Scholar 

  • Chung KF (2001) Cytokines in chronic obstructive pulmonary disease. Eur Respir J 18:S50

    Article  CAS  Google Scholar 

  • DeMeo DL, Celedon JC, Lange C, Reilly JJ, Chapman HA, Sylvia JS, Speizer FE, Weiss ST, Silverman EK (2004) Genome-wide linkage of forced mid-expiratory flow in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 170:1294

    Article  PubMed  Google Scholar 

  • den Dunnen JT, Antonarakis E (2001) Nomenclature for the description of human sequence variations. Hum Genet 109:121

    Article  CAS  Google Scholar 

  • Fletcher C, Peto R (1977) The natural history of chronic airflow obstruction. Br Med J 1:1645

    Article  PubMed  CAS  Google Scholar 

  • Foss L, Pare PD, Sandford AF (2002) Genetic risk factors for chronic obstructive pulmonary disease. Swiss Med Wkly 132:27

    Google Scholar 

  • Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, Altshuler D (2002) The structure of haplotype blocks in the human genome. Science 296:2225

    Article  PubMed  CAS  Google Scholar 

  • Greenwood CM, Fujiwara TM, Boothroyd LJ, Miller MA, Frappier D, Fanning EA, Schurr E, Morgan K (2000) Linkage of tuberculosis to chromosome 2q35 loci, including NRAMP1, in a large aboriginal Canadian family. Am J Hum Genet 67:405

    Article  PubMed  CAS  Google Scholar 

  • Hersh CP, DeMeo DL, Lange C, Litonjua AA, Reilly JJ, Kwiatkowski D, Laird N, Sylvia JS, Sparrow D, Speizer FE, Weiss ST, Silverman EK (2005) Attempted replication of reported chronic obstructive pulmonary disease candidate gene associations. Am J Respir Cell Mol Biol 33:71

    Article  PubMed  CAS  Google Scholar 

  • Kim JH, Lee SY, Lee SH, Sin C, Shim JJ, In KH, Yoo SH, Kang KH (2003) NRAMP1 genetic polymorphisms as a risk factor of tuberculous pleurisy. Int J Tuberc Lung Dis 7:370

    PubMed  CAS  Google Scholar 

  • Kim SK, Jang WC, Park SB, Park DY, Bang KT, Lee SS, Jun JB, Yoo DH, Chang HK (2006) SLC11A1 gene polymorphisms in Korean patients with Behcet’s disease. Scand J Rheumatol 35:398

    Article  PubMed  CAS  Google Scholar 

  • Liu J, Fujiwara TM, Buu NT, Sanchez FO, Cellier M, Paradis AJ, Frappier D, Skamene E, Gros P, Morgan K et al (1995) Identification of polymorphisms and sequence variants in the human homologue of the mouse natural resistance-associated macrophage protein gene. Am J Hum Genet 56:845

    PubMed  CAS  Google Scholar 

  • Malhotra A, Peiffer AP, Ryujin DT, Elsner T, Kanner RE, Leppert MF, Hasstedt SJ (2003) Further evidence for the role of genes on chromosome 1 and chromosome 5 in the inheritance of pulmonary function. Am J Respir Crit Care Med 168:556

    Article  PubMed  Google Scholar 

  • Ouchi K, Suzuki Y, Shirakawa T, Kishi F (2003) Polymorphism of SLC11A1 (formerly NRAMP1) gene confers susceptibility to Kawasaki disease. J Infect Dis 187:83

    Article  Google Scholar 

  • Palmer LJ, Celedon JC, Chapman HA, Speizer FE, Weiss ST, Silverman EK (2003) Genome-wide linkage analysis of bronchodilator responsiveness and post-bronchodilator spirometric phenotypes in chronic obstructive pulmonary disease. Hum Mol Genet 12:1199

    Article  PubMed  CAS  Google Scholar 

  • Parks SB, Popovich BW, Press RD (2001) Real-time polymerase chain reaction with fluorescent hybridization probes for the detection of prevalent mutations causing common thrombophilic and iron overload phenotypes. Am J Clin Pathol 115:439

    Article  PubMed  CAS  Google Scholar 

  • Pauwels RA, Buist AS, Calverley PMA, Jenkins CR, Hurd SS (2001) Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 163:1256

    PubMed  CAS  Google Scholar 

  • Romero-Gomez M, Montes-Cano MA, Otero-Ferandez MA, Torres B, Barroso N, Gomez-Izquierdo L, Castellano-Megias VM, Nunez-Roldan A, Aguilar-Reina J, Gonzalez-Excribano MF (2004) SLC11A1 promoter gene polymorphisms and fibrosis progression in chronic hepatitis C. Gut 53:446

    Article  PubMed  CAS  Google Scholar 

  • Sechi LA, Gazouli M, Sieswerda LE, Molicotti P, Ahmed N, Ikonomopoulos J, Scanu AM, Paccagnini D, Zanetti S (2006) Relationship between Crohn’s disease with Mycobacterium avium subspecies paratuberculosis and SLC11A1 gene polymorphisms in Sardinian patients. World J Gastroenterol 12:7161

    PubMed  CAS  Google Scholar 

  • Searle S, Blackwell JM (1999) Evidence for a functional repeat polymorphism in the promoter of the human NRAMP1 gene that correlates with autoimmune versus infectious disease susceptibility. J Med Genet 36:295

    PubMed  CAS  Google Scholar 

  • Shapiro SD (1999) The macrophage in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 160:S29

    PubMed  CAS  Google Scholar 

  • Shirakawa T, Kishi F (2000) Genetic variants of NRAMP1 and active tuberculosis in Japanese populations. Clin Genet 58:74

    Article  PubMed  Google Scholar 

  • Silverman EK, Chapman HA, Drazen JM, Weiss ST, Rosner B, Campbell EJ, O’Donnell WJ, Reilly JJ, Ginns L, Mentzer S, Wain J, Speizer FE (1998) Genetic epidemiology of severe, early-onset chronic obstructive pulmonary disease. Am J Respir Crit Care Med 157:1770

    PubMed  CAS  Google Scholar 

  • Silverman EK, Palmer LJ, Mosley JD, Barth M, Senter JM, Brown A, Drazen JM, Kwiatkowski DJ, Chapman HA, Campbell EJ, Province MA, Rao DC, Reilly JJ, Ginns LC, Speizer FE, Weiss ST (2002) Genomewide linkage analysis of quantitative spirometric phenotypes in severe early-onset chronic obstructive pulmonary disease. Am J Hum Genet 70:1229

    Article  PubMed  CAS  Google Scholar 

  • Stephens M, Smith MJ, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68:978

    Article  PubMed  CAS  Google Scholar 

  • Yang YS, Kim SJ, Kim JW, Koh EM (2000) NRAMP1 gene polymorphisms in patients with rheumatoid arthritis. J Korean Med Sci 15:83

    PubMed  CAS  Google Scholar 

  • Zaahl MG, Robson KJH, Warnich L, Kotze MJ (2004) Expression of the SLC11A1 (NRAMP1) 5′-(GT)n repeat; opposite effect in the presence of −237C → T. Blood Cells Mol Dis 33:45

    Article  PubMed  CAS  Google Scholar 

  • Zaahl MG, Winter TA, Warnich L, Kotze MJ (2006) The −237C → T promoter polymorphism of the SLC11A1 gene is associated with a protective effect in relation to inflammatory bowel disease in the South African population. Int J Colorectal Dis 21:402

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (A060165), and in part by the Brain Korea 21 Project in 2006.

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Kyungpook National University Hospital, Samduk 2 Ga 50, Daegu, 700-412, South Korea

    Eun Jin Kim, Sung Ick Cha, Chang Ho Kim, Young Mo Kang, Tae Hoon Jung & Jae Yong Park

  2. Department of Biochemistry, Kyungpook National University School of Medicine, Daegu, South Korea

    Kyung Mee Kim, Sun Ha Park, Jong Sik Kim & Jae Yong Park

  3. Department of Preventive Medicine, Kyungpook National University School of Medicine, Daegu, South Korea

    Won Kee Lee

  4. Department of Internal Medicine, School of Medicine, Keimyung University, Daegu, South Korea

    Sung Beom Han

Authors
  1. Eun Jin Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kyung Mee Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sun Ha Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jong Sik Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Won Kee Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sung Ick Cha
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chang Ho Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Young Mo Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sung Beom Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Tae Hoon Jung
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jae Yong Park
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jae Yong Park.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kim, E.J., Kim, K.M., Park, S.H. et al. SLC11A1 Polymorphisms Are Associated with the Risk of Chronic Obstructive Pulmonary Disease in a Korean Population. Biochem Genet 46, 506–519 (2008). https://doi.org/10.1007/s10528-008-9166-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10528-008-9166-6

Keywords

Search

Navigation